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HMG-CoA reductase inhibitors enhance phagocytosis by upregulating ATP-binding cassette transporter A7
Abstract
We recently reported that the endogenous ATP-binding cassette transporter (ABC) A7 strongly associates with phagocytosis, being regulated by sterol regulatory element binding protein 2. We therefore examined the effect of statins on phagocytosis in vitro and in vivo through the SREBP-ABCA7. Phagocytosis was found to be enhanced by pravastatin, rosuvastatin and simvastatin and cyclodextrin in J774 macrophages, as cellular cholesterol was reduced and expressions of the cholesterol-related genes were modulated, including an increase of ABCA7 mRNA and decrease of ABCA1 mRNA. Conversely, knock-down of ABCA7 expression by siRNA ablated enhancement of phagocytosis by statins. In vivo, pravastatin enhanced phagocytosis in wild-type mice, but not in ABCA7-knockout mice. We thus concluded that statins enhance phagocytosis through the SREBP-ABCA7 pathway. These findings provide a molecular basis for enhancement of the host-defense system by statins showing that one of their "pleiotropic" effects is in fact achieved through their reaction to a primary target.
... The ATP-binding cassette transporter (ABC) A7 is linked to phagocytosis, which is regulated through sterol-responsive/regulatory element binding protein-2 (SREBP-2) (Tanaka, Abe-Dohmae, Iwamoto, Fitzgerald, & Yokoyama, 2011). ABCA7 has an important role in efferocytosis (Jehle et al., 2006). ...
... ABCA7 has an important role in efferocytosis (Jehle et al., 2006). The effect of statins on phagocytosis via the SREBP-ABCA7 pathway has been shown in vitro and in vivo (Tanaka et al., 2011). Phagocytosis has been shown to be enhanced by pravastatin (50 μM), simvastatin (10 μM), and rosuvastatin (5 μM) in vitro. ...
... Accordingly, cellular cholesterol levels were decreased, and the expression of cholesterol-related genes were modulated, such as increased mRNA levels of ABCA7 and decreased mRNA levels of ABCA1. In vivo, pravastatin (50 μM) did not enhance phagocytosis in ABCA7-knockout mice (Tanaka et al., 2011). ...
Efferocytosis (clearance of apoptotic cells by phagocytosis without inducing inflammation and autoimmunity) is an important mechanism in the resolution of inflammatory processes. Efficient efferocytosis inhibits the accumulation of apoptotic cells/debris and maintains homeostasis before the onset of necrosis (secondary necrosis), which promotes inflammation or injury. Moreover, the detection and clearance of apoptotic cells can promote anti-inflammatory responses. Defective efferocytosis is involved in the pathogenesis of several diseases, such as atherosclerosis, chronic inflammation, autoimmunity and cancer. Statins are 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors which exert cholesterol-lowering effects plus multiple pleiotropic properties, such as inhibition of inflammation and macrophage proliferation. Statins exhibit anti-inflammatory properties by reducing both the prenylation of signaling molecules with downregulation of gene expression and the expression of adhesion molecules, as well as the levels of cytokines and chemokines. Additionally, statins suppress the prenylation of GTPases, such as Rac-1, as a positive regulator of efferocytosis, and RhoA, as a negative regulator of efferocytosis. However, statins alter the membrane balance of Rho GTPases in efferocytosis toward Rac-1. Efferocytosis has modifiable targets, which can be exploited for the treatment of several diseases, although limited attention has been given to the mechanisms by which statins regulate efferocytosis and the resulting therapeutic implications. In this review, we will elaborate on the mechanisms underlying the modulation of apoptotic cell clearance by statins, which, in turn, inhibits uncontrolled inflammation and ensuing diseases.
... The ATP-binding cassette transporter (ABC) A7 is linked to phagocytosis, which is regulated through sterol-responsive/regulatory element binding protein-2 (SREBP-2) (Tanaka, Abe-Dohmae, Iwamoto, Fitzgerald, & Yokoyama, 2011). ABCA7 has an important role in efferocytosis (Jehle et al., 2006). ...
... ABCA7 has an important role in efferocytosis (Jehle et al., 2006). The effect of statins on phagocytosis via the SREBP-ABCA7 pathway has been shown in vitro and in vivo (Tanaka et al., 2011). Phagocytosis has been shown to be enhanced by pravastatin (50 μM), simvastatin (10 μM), and rosuvastatin (5 μM) in vitro. ...
... Accordingly, cellular cholesterol levels were decreased, and the expression of cholesterol-related genes were modulated, such as increased mRNA levels of ABCA7 and decreased mRNA levels of ABCA1. In vivo, pravastatin (50 μM) did not enhance phagocytosis in ABCA7-knockout mice (Tanaka et al., 2011). ...
... In addition, certain compounds were also demonstrated to interfere with Abca7 expression. 205,431 These include pravastatin 205,431 and rosuvastatin (Figure 2). 431 These agents increased Abca7 mRNA and ABCA7 protein levels in vitro, 205,431 whilst pravastatin had the same effects in vivo in murine peritoneal macrophages. ...
... 205,431 These include pravastatin 205,431 and rosuvastatin (Figure 2). 431 These agents increased Abca7 mRNA and ABCA7 protein levels in vitro, 205,431 whilst pravastatin had the same effects in vivo in murine peritoneal macrophages. 431 Surprisingly, this increase of Abca7 mRNA and ABCA7 protein levels was accompanied by a downregulation of Lxra and upregulation of Srebp2 in vitro. ...
... 205,431 These include pravastatin 205,431 and rosuvastatin (Figure 2). 431 These agents increased Abca7 mRNA and ABCA7 protein levels in vitro, 205,431 whilst pravastatin had the same effects in vivo in murine peritoneal macrophages. 431 Surprisingly, this increase of Abca7 mRNA and ABCA7 protein levels was accompanied by a downregulation of Lxra and upregulation of Srebp2 in vitro. ...
Adenosine-triphosphate-(ATP)-binding cassette (ABC) transport proteins are ubiquitously present membrane-bound efflux pumps that distribute endo- and xenobiotics across intra- and intercellular barriers. Discovered over 40 years ago, ABC transporters have been identified as key players in various human diseases, such as multidrug-resistant cancer and atherosclerosis, but also neurodegenerative diseases, such as Alzheimer’s disease (AD). Most prominent and well-studied are ABCB1, ABCC1, and ABCG2, not only due to their contribution to the multidrug resistance (MDR) phenotype in cancer, but also due to their contribution to AD. However, our understanding of other ABC transporters is limited, and most of the 49 human ABC transporters have been largely neglected as potential targets for novel small-molecule drugs. This is especially true for the ABCA subfamily, which contains several members known to play a role in AD initiation and progression. This review provides up-to-date information on the proposed functional background and pathological role of ABCA transporters in AD. We also provide an overview of small-molecules shown to interact with ABCA transporters as well as potential in silico, in vitro, and in vivo methodologies to gain novel templates for the development of innovative ABC transporter-targeting diagnostics and therapeutics.
... While statins were characterized for their inhibition of cholesterol biosynthesis and lowering of blood cholesterol levels, subsequent mechanistic studies have suggested much of their action in reducing risks for cardiovascular disease are unrelated to cholesterol levels, relating rather to pleiotropic effects including isoprenoid biosynthesis and subsequent protein prenylation [22,23]. Studies of blood derived monocytes and macrophages have highlighted a number of anti-inflammatory effects of statins including altered cytokine release and phagocytic activity [24][25][26][27][28][29]. In the CNS statin treatment has been suggested to delay the onset and slow the progression of Alzheimer's disease and dementia [30][31][32], and statin treatment after ischemic stroke and thrombolysis has recently been shown to improve functional outcomes and reduce risk of neurological deterioration and death [33]. ...
... Studies in rodents have shown statin treatment improved outcomes in models of ischemic stroke [34,35], intracerebral hemorrhage [36], traumatic brain injury [37], and Alzheimer's disease [38,39]. Despite a wealth of evidence that statins directly modulate macrophage function [24][25][26][27][28][29] and observation of changes in microglial and inflammatory markers in the CNS after statin treatment [35][36][37][38][39] studies of the direct effects of statin treatment on microglia have been sparing, and present conflicting data. In primary rodent microglial cultures, lovastatin decreased release of inflammatory mediators nitric oxide (NO), tumour necrosis factor-α (TNFα), and interleukin-1β (Il1β) [40] and simvastatin treatment decreased surface antigen expression including major histocompatibility complex II (MHCII) and chemokine receptor CXCR3 [41] while in primate microglial cultures simvastatin increased secretion of cytokines (TNFα, Il1β, interleukin-12, and interleukin-6) [42] and in rat hippocampal slice cultures mevastatin treatment increased cytokine release and surface antigen expression (TNFα, cluster of differentiation[CD]-11b) [43]. ...
... Kuipers and colleagues [41] demonstrated inhibitory effects of statin treatment on cytoskeletal dynamics and motility in primary microglial culturesboth of which would contribute to phagocytic mechanisms, but stopped short of testing phagocytosis. Others report enhancement of phagocytosis after statin treatment of rodent peritoneal macrophages [28,29] and human blood derived monocytes [27]. Reports are likewise mixed as to the mechanism of statin mediated inhibition of phagocytosis, with two showing rescue with cholesterol [25,28], two with MEV alone [41,59], and one with MEV but not squalene, the first committed intermediate in cholesterol synthesis [24]. ...
Background
As the primary immune cells of the central nervous system, microglia contribute to development, homeostasis, and plasticity of the central nervous system, in addition to their well characterized roles in the foreign body and inflammatory responses. Increasingly, inappropriate activation of microglia is being reported as a component of inflammation in neurodegenerative and neuropsychiatric disorders. The statin class of cholesterol-lowering drugs have been observed to have anti-inflammatory and protective effects in both neurodegenerative diseases and ischemic stroke, and are suggested to act by attenuating microglial activity.ResultsWe sought to investigate the effects of simvastatin treatment on the secretory profile and phagocytic activity of primary cultured rat microglia, and to dissect the mechanism of action of simvastatin on microglial activity. Simvastatin treatment altered the release of cytokines and trophic factors from microglia, including interleukin-1-ß, tumour necrosis factor-¿, and brain derived neurotrophic factor in a cholesterol-dependent manner. Conversely, simvastatin inhibited phagocytosis in microglia in a cholesterol-independent manner.Conclusions
The disparity in cholesterol dependence of cytokine release and phagocytosis suggests the two effects occur through distinct molecular mechanisms. These two pathways may provide an opportunity for further refinement of pharmacotherapies for neuroinflammatory, neurodegenerative, and neuropsychiatric disorders.
... Besides the substrates cholesterol and phospholipids [12,13,24,34], the only small-molecules associated with ABCA7 are regulators of ABCA7 expression. These regulators include the inducers ponasterone A [39], pravastatin [40,41], and rosuvastatin [40], as well as the downregulators digoxin [42] and 25hydroxycholesterol [43] (all Fig. 1). These regulators are only of very limited use to monitor and/or influence the transport process, as they do not directly interact with ABCA7. ...
... Besides the substrates cholesterol and phospholipids [12,13,24,34], the only small-molecules associated with ABCA7 are regulators of ABCA7 expression. These regulators include the inducers ponasterone A [39], pravastatin [40,41], and rosuvastatin [40], as well as the downregulators digoxin [42] and 25hydroxycholesterol [43] (all Fig. 1). These regulators are only of very limited use to monitor and/or influence the transport process, as they do not directly interact with ABCA7. ...
The adenosine-triphosphate-(ATP)-binding cassette (ABC) transporter ABCA7 is a genetic risk factor for Alzheimer’s disease (AD). Defective ABCA7 promotes AD development and/or progression. Unfortunately, ABCA7 belongs to the group of ‘under-studied’ ABC transporters that cannot be addressed by small-molecules. However, such small-molecules would allow for the exploration of ABCA7 as pharmacological target for the development of new AD diagnostics and therapeutics. Pan-ABC transporter modulators inherit the potential to explore under-studied ABC transporters as novel pharmacological targets by potentially binding to the proposed ‘multitarget binding site’. Using the recently reported cryo-electron microscopy (cryo-EM) structures of ABCA1 and ABCA4, a homology model of ABCA7 has been generated. A set of novel, diverse, and potent pan-ABC transporter inhibitors has been docked to this ABCA7 homology model for the discovery of the multitarget binding site. Subsequently, application of pharmacophore modelling identified the essential pharmacophore features of these compounds that may support the rational drug design of innovative diagnostics and therapeutics against AD.
... HEK293 cells were transfected with these constructs and the resulting luminescence was measured after treatment with mevastatin or vehicle. Mevastatin was used in order to activate cellular ABCA7 machinery since it had been shown that cholesterol depletion stimulates SREBP2 expression which activates ABCA7 expression machinery [23,34]. HEK293 cells transfected with int13-T exhibited increased luminescence after mevastatin treatment relative to vector control ( Fig. 2B, one-way ANOVA, Bonferroni post-hoc test * * p < 0.01). ...
... However, the association between clinical presentation and ABCA7 levels has generated conflicting results. It was reported that higher ABCA7 levels were associated with more advanced cognitive decline [34,42,43]. Yet, it was suggested that increased ABCA7 expression reduces AD risk [17,23,24], and recently, that altered DNA methylation at the ABCA7 locus was associated with pathological AD diagnosis [44]. ...
Alzheimer's disease (AD) is characterized by extracellular deposits of amyloid-β (Aβ) in the brain. ABCA7 is highly expressed in the brain and a susceptibility gene for late-onset AD (LOAD). The minor alleles at two ABCA7 single-nucleotide polymorphisms (SNPs), rs3764650 (T>G; intron13) and rs3752246 at a predicted myristoylation site (C>G; exon33; p.Gly1527Ala), are significantly associated with LOAD risk; however, the mechanism of this association is unknown. Functional consequences of both SNPs were examined in HEK293 and CHO cells stably expressing AβPPSwe. Luciferase reporter assays in HEK293 cells suggested that intron13 carrying rs3764650 major T-allele (int13-T) possessed promoter-enhancing capabilities. Co-transfection experiments with hABCA7 and int13-T resulted in significantly increased ABCA7 protein level relative to that with int13-G. Expression of hABCA7 carrying rs3752246 risk allele led to increases in secreted Aβ40 and Aβ42 and β-secretase activity in CHO- and HEK-AβPPSwe cells. Hydroxymyristic acid treatment of cells expressing hABCA7 carrying the rs3752246 major G allele resulted in increased β-secretase activity and levels of Aβ, suggesting that lack of myristoylation contributes to observed cell-phenotypes. Molecular weight determination, by gel-electrophoresis and mass spectrometry, of hABCA7 peptides spanning position 1527 showed loss of post-translational modification in the risk-allele peptide. These results suggest that decreased expression, or impaired function, of ABCA7 may contribute to AD pathology.
... Statin's pharmacological action is based on decreasing the level of cholesterol synthesis. In addition, they up regulate the LDL-C-receptor gene through the sterol regulatory element binding protein (SREBP) system that senses cellular cholesterol levels, causing a marked LDL-C reduction (20%–55%), moderate reduction of triglycerides (8%–30%) and producing minor increases in HDL-C (2%–10%)78910111213. Statins also reduce levels of atherogenic lipoproteins by inhibiting hepatic synthesis of Apo lipoprotein B100 and reducing the synthesis and secretion of triglyceride-rich lipoproteins [14, 15]. ...
... The gene expression of the ABCA7 is regulated by cellular sterol via the SREBP system and is stabilized by helical apo lipoproteins, resulting in an increase of phagocytosis. These findings provide a molecular basis for host-defense system boosting by statins, indicating that one of their pleiotropic effects is achieved through their reaction with a primary target [12, 43, 44]. Despite the wide use of statins, they have side effects. ...
Cardiovascular diseases (CVD) are common and very well-known diseases that affect a large number of people. One of the common leading causes of CVD is a high level of lipids which eventually leads to atherosclerosis and CVD. Various types of medications having different mechanisms of action were introduced to control CVD. Among the frequently used drugs is statins. Statins have a very intense effect on lowering lipids, yet they are associated with a variety of side effects. Moreover, statins have low bioavailability, similarly to other lipid lowering medications. Therefore, several attempts were made to enhance their bioavailability. This chapter discusses a number of drugs used to lower lipid levels in the blood, their adverse effects and methods to improve their bioavailability.
... Along with the sustained efforts to elucidate the role of ABCA7 in cellular lipid transport, evidence has accumulated during the past years that links another potential function of this transporter to neurodegenerative disease. Recent reports indicate a central role of ABCA7 in phagocytosis and the engulfment of apoptotic cells (Iwamoto et al., 2006; Jehle et al., 2006; Tanaka et al., 2010 Tanaka et al., , 2011a ,b). In addition to the finding that ABCA7 mRNA and protein is up-regulated during phagocytosis via the SREBP2 pathway (Iwamoto et al., 2006), these studies showed that knock-down of ABCA7 results in a decreased phagocytic activity (Iwamoto et al., 2006) and that heterozygous ABCA7+/− mice exhibit a defective clearance of apoptotic cells (Jehle et al., 2006). ...
... Another study by the same group also demonstrated that statin treatment of J774 cells induces ABCA7 expression by its cholesterol-lowering effect and simultaneously enhances phagocytosis . This increase in phagocytic activity was abolished by ABCA7 siRNA treatment of the statin stimulated cells (Tanaka et al., 2011a). The finding that ABCA7 promotes Fc receptor-independent phagocytosis is of particular interest taking into account that human microglia cells contribute to the phagocytic removal of apoptotic debris from the brain (Stolzing and Grune, 2004; Napoli and Neumann, 2009) and given that among brain cells microglia displays highest ABCA7 expression. ...
The A-subclass of ATP-binding cassette (ABC) transporters comprises 12 structurally related members of the evolutionarily highly conserved superfamily of ABC transporters. ABCA transporters represent a subgroup of “full-size” multispan transporters of which several members have been shown to mediate the transport of a variety of physiologic lipid compounds across membrane barriers. The importance of ABCA transporters in human disease is documented by the observations that so far four members of this protein family (ABCA1, ABCA3, ABCA4, ABCA12) have been causatively linked to monogenetic disorders including familial high-density lipoprotein deficiency, neonatal surfactant deficiency, degenerative retinopathies, and congenital keratinization disorders. Recent research also point to a significant contribution of several A-subfamily ABC transporters to neurodegenerative diseases, in particular Alzheimer’s disease (AD). This review will give a summary of our current knowledge of the A-subclass of ABC transporters with a special focus on brain lipid homeostasis and their involvement in AD.
... Statins that reduced cellular lipids caused an upregulation of ABCA7, followed by increased phagocy-tosis in vitro. 119 Moreover, ABCA7 can influence composition and asymmetric distribution of the lipid bilayer, such as increased lipid flipping of phosphatidylserine from the cytoplasmic to the extracellular leaflet, creating an "eat-me" signal in apoptotic cells ( Figure 4). 13,109 An enrichment of phosphatidylserine on the extracellular surface has been linked to phagocytosis and assembly of phagocytosis-associated protein at the membrane. ...
Alzheimer's disease (AD) is a growing problem worldwide. Since ABCA7’s identification as a risk gene, it has been extensively researched for its role in the disease. We review its recently characterized structure and what the mechanistic insights teach us about its function. We furthermore provide an overview of identified ABCA7 mutations, their presence in different ancestries and protein domains and how they might cause AD. For ABCA7 PTC variants and a VNTR expansion, haploinsufficiency is proposed as the most likely mode‐of‐action, although splice events could further influence disease risk. Overall, the need to better understand expression of canonical ABCA7 and its isoforms in disease is indicated. Finally, ABCA7's potential functions in lipid metabolism, phagocytosis, amyloid deposition, and the interplay between these three, is described. To conclude, in this review, we provide a comprehensive overview and discussion about the current knowledge on ABCA7 in AD, and what research questions remain.
Highlights
Alzheimer's risk‐increasing variants in ABCA7 can be found in up to 7% of AD patients.
We review the recently characterized protein structure of ABCA7.
We present latest insights in genetics, expression patterns, and functions of ABCA7.
... Recent results from cell lipid efflux assays and shotgun lipid mass spectrometry suggest that ABCA7 has lower specificity for phosphatidylcholine, similar preference for cholesterol, and higher preference for non-choline-containing phospholipids compared to ABCA1 [13]. Several studies hint at a function of ABCA7, but not of ABCA1, in phagocytosis of apoptotic cells [9,14,15]. ...
The ABC transporter ABCA7 has been found to be aberrantly expressed in a variety of cancer types, including breast cancer. We searched for specific epigenetic and genetic alterations and alternative splicing variants of ABCA7 in breast cancer and investigated whether these alterations are associated with ABCA7 expression. By analyzing tumor tissues from breast cancer patients, we found CpGs at the exon 5–intron 5 boundary aberrantly methylated in a molecular subtype-specific manner. The detection of altered DNA methylation in tumor-adjacent tissues suggests epigenetic field cancerization. In breast cancer cell lines, DNA methylation levels of CpGs in promoter exon 1, intron 1, and at the exon 5–intron 5 boundary were not correlated with ABCA7 mRNA levels. By qPCR involving intron-specific and intron-flanking primers, we identified intron-containing ABCA7 mRNA transcripts. The occurrence of intron-containing transcripts was neither molecular subtype-specific nor directly correlated with DNA methylation at the respective exon–intron boundaries. Treatment of breast cancer cell lines MCF-7, BT-474, SK-BR3, and MDA-MB-231 with doxorubicin or paclitaxel for 72 h resulted in altered ABCA7 intron levels. Shotgun proteomics revealed that an increase in intron-containing transcripts was associated with significant dysregulation of splicing factors linked to alternative splicing.
... Both in vitro and in vivo studies show abolished phagocytosis in Abca7 deficient mouse macrophages, while phagocytosis was not altered in ABCA1 deficient cells [117,122]. Decreasing cellular lipid content using statins was found to enhance phagocytosis via upregulation of ABCA7 in vitro and in mice, indicating a direct link between cholesterol homeostasis and phagocytosis [123]. Mechanistically, ABCA7 and low-density lipoprotein receptor-related protein 1 (LRP1) colocalize at the cell surface of macrophages after stimulation by apoptotic cells. ...
Background
Alzheimer’s disease (AD) is the leading cause of dementia, clinically characterized by memory deficits and progressive cognitive decline. Despite decades of research effective therapies are lacking, and a large part of the genetic heritability remains unidentified. ABCA7 and ABCA1 , members of the ATP-binding cassette subfamily A (ABCA), were identified as AD risk genes in genome-wide association studies. Nevertheless, genetic and/or functional studies propose a link between AD and two other members of the ABCA subclass, i.e., ABCA2 and ABCA5.
Main body
Changes in expression or dysfunction of these transporters were found to increase amyloid β levels. This might be related to the common role of ABCA transporters in cellular cholesterol homeostasis, for which a prominent role in AD development has been suggested. In this review, we provide a comprehensive overview and discussion on the contribution of the ABCA subfamily to the etiopathogenesis of AD.
Conclusions
A better understanding of the function and identification of disease-associated genetic variants in ABCA transporters can contribute to the development of novel therapeutic strategies for AD.
... These findings are in accordance with published data for human macrophages [20], murine peritoneal macrophages, and human monocytes [62]. Interestingly, other experimental setups with in vivo and ex vivo murine peritoneal macrophages suggested an enhanced phagocytotic activity upon statin treatment, which might be related to differences regarding the macrophage origin or the phagocytosed material [63,64]. Mechanistically, statins may impair phagocytosis via reduced isoprenylation of members of the Rho family of small G-proteins, as shown in previous studies [65,66]. ...
Statins represent the most prescribed class of drugs for the treatment of hypercholesterolemia. Effects that go beyond lipid-lowering actions have been suggested to contribute to their beneficial pharmacological properties. Whether and how statins act on macrophages has been a matter of debate. In the present study, we aimed at characterizing the impact of statins on macrophage polarization and comparing these to the effects of bempedoic acid, a recently registered drug for the treatment of hypercholesterolemia, which has been suggested to have a similar beneficial profile but fewer side effects. Treatment of primary murine macrophages with two different statins, i.e., simvastatin and cerivastatin, impaired phagocytotic activity and, concurrently, enhanced pro-inflammatory responses upon short-term lipopolysaccharide challenge, as characterized by an induction of tumor necrosis factor (TNF), interleukin (IL) 1β, and IL6. In contrast, no differences were observed under long-term inflammatory (M1) or anti-inflammatory (M2) conditions, and neither inducible NO synthase (iNOS) expression nor nitric oxide production was altered. Statin treatment led to extracellular-signal regulated kinase (ERK) activation, and the pro-inflammatory statin effects were abolished by ERK inhibition. Bempedoic acid only had a negligible impact on macrophage responses when compared with statins. Taken together, our data point toward an immunomodulatory effect of statins on macrophage polarization, which is absent upon bempedoic acid treatment.
... Numerous studies have demonstrated the anti-inflammatory effects of statins in altering cytokine release and phagocytic activity. [40][41][42][43][44][45] Simvastatin has been shown to be superior to alternative statins in preventing neurodegenerative conditions, because of its permeability across the blood-brain barrier and ability to prevent cell death. 46 Moreover, TRD has been shown to be a neuroprogressive condition 47 yet despite clinical trials demonstrating simvastatin's potential efficacy as an adjuvant treatment for MDD, 22 we are unaware of any clinical trials in TRD. ...
Background
A third of patients diagnosed with major depressive disorder (MDD) experience treatment-resistant depression (TRD). Relatively few pharmacological agents have established efficacy for TRD. Therefore, the evaluation of novel treatments for TRD is a pressing priority. Statins are pleiotropic agents and preclinical studies as well as preliminary clinical trials have suggested that these drugs may have antidepressant properties.
Aims
To report on a protocol for a 12-week, randomised, double-blind, placebo-controlled trial of add-on treatment with simvastatin for patients meeting DSM-5 criteria for MDD who have failed to respond to at least two adequate trials with approved antidepressants. The trial has been registered with Clinicaltrials.gov in (ClinicalTrials.gov identifier: NCT03435744).
Method
After screening and randomisation to the two parallel arms of the trial, 75 patients will receive simvastatin and 75 patients will receive placebo as adjuncts to treatment as usual. The primary outcome is change in Montgomery–Åsberg Depression Rating Scale scores from baseline to week 12 and secondary outcomes include changes in scores on the 24-item Hamilton Rating Scale for Depression, the Clinical Global Impression scale, the 7-item Generalized Anxiety Disorder scale and change in body mass index from baseline to week 12. Assessments will take place at screening, baseline, and weeks 2, 4, 8 and 12. Checklists for adverse effects will be undertaken at each visit. Simvastatin (20 mg) will be given once daily. Other secondary outcomes include C-reactive protein and plasma lipids measured at baseline and week 12.
Results
This trial will assess simvastatin's efficacy and tolerability as an add-on treatment option for patients with TRD and provide insights into its putative mechanisms of action.
Conclusions
As the first trial investigating the use of simvastatin as an augmentation strategy in patients with TRD, if the results indicate that adjuvant simvastatin is efficacious in reducing depressive symptoms, it will deliver immediate clinical benefit.
Declaration of interest
I.B.C. and N.H. have given lectures and advice to Eli Lilly, Bristol Myers Squibb, Lundbeck, Astra Zeneca and Janssen pharmaceuticals for which they or their employing institution have been reimbursed. R.R. and M.M.H. have received educational grants and support for academic meetings from Pfizer, Roche, Novartis and Nabiqasim. A.H.Y. has been commissioned to provide lectures and advice to all major pharmaceutical companies with drugs used in affective and related disorders. A.H.Y. has undertaken investigator-initiated studies from Astra Zeneca, Eli Lilly, Lundbeck and Wyeth. None of the companies have a financial interest in this research.
... 9 Although there is little evidence that de novo administration of statins can significantly improve the outcomes of infections, they appeared to influence the course of infections indirectly. This may occur via the mechanisms affecting the rate of phagocytosis, 10 stimulation of production of neutrophil extracellular traps, 11 or inhibition of bacterial escape from phagosomes in concert with promoting antiinflammatory mechanisms. 12 Direct microbicidal effects of statins for numerous bacterial species were also reported. ...
Background
Statins effectively reduce risk of cardiovascular‐related morbidity and mortality in patients with hyperlipidemia, hypertension or type‐II diabetes. In addition to lowering cholesterol levels, several studies have attributed statins with immunomodulatory and bactericidal properties. Therefore, the aim of this study was to investigate statins' antimicrobial activity against relevant for periodontal homeostasis bacteria.
Methods
Statin effect on bacterial growth was tested using planktonic monocultures and multibacterial biofilms. The latter consisted of five microbial species (Porphyromonas gingivalis, Fusobacterium nucleatum, Actinomyces naeslundii, Tannerella forsythia, Streptococcus gordonii) associated with dysbiosis of the oral microbiota underlying establishment and perpetuation of periodontitis.
Results
All four tested statins efficiently inhibited P. gingivalis growth and significantly decreased the cumulative bacterial load in developing and established biofilms. Simvastatin was most efficient and decreased P. gingivalis counts more than 1300‐fold relative to the control.
Conclusions
These findings suggest that similar effects on bacterial composition of the dental plaque may occur in vivo in patients on statins thus leading to a shift of the oral microbiome from a dysbiotic to a more homeostatic one. Simvastatin, being highly effective against P. gingivalis while not affecting commensal microbiota, possesses many properties qualifying it as a potential adjunctive treatment for chronic periodontitis. Further studies are needed to evaluate whether similar effects on bacterial composition of the dental plaque may occur in vivo in patients on statins thus leading to a shift of the oral microflora from dysbiotic to a more homeostatic one.
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... It has been documented that statins have the capacity to act as immunomodulators. For example, statins induce the phagocytic activity of macrophage J774 [65]. It has also been reported that they act as inhibitors of the expression of MHCII induced by IFN-γ in primary endothelial cells, monocytes, and human macrophages, which in turn inhibits the activation of T lymphocytes [66]. ...
Tuberculosis is one of the 10 leading causes of death in the world. The current treatment is based on a combination of antimicrobials administered for six months. It is essential to find therapeutic agents with which the treatment time can be shortened and strengthen the host immune response against Mycobacterium tuberculosis . M. tuberculosis needs cholesterol to infect and survive inside the host, but the progression of the infection depends to a large extent on the capacity of the immune response to contain the infection. Statins inhibit the synthesis of cholesterol and have pleiotropic effects on the immune system, which have been associated with better results in the treatment of several infectious diseases. Recently, it has been reported that cells treated with statins are more resistant to M. tuberculosis infection, and they have even been proposed as adjuvants in the treatment of M. tuberculosis infection. The aim of this review is to summarize the immunopathogenesis of tuberculosis and its mechanisms of evasion and to compile the available scientific information on the effect of statins in the treatment of tuberculosis.
... For example, the reduction of Hmgcr impaired differentiation ( Figure 2A) and migration ( Figure 3D), as was reported for statin treatment. 37,38 However, other effects of statins such as alterations in adhesion, 39 phagocytosis, 40 and cytokine secretion 41 were not observed in our study. Of course, these differences might result from the different methods of inhibiting HMGCR: drugs and genetic manipulation. ...
... Rosuvastatin inhibited the proinflammatory markers such as TNF-α and IL-1β, upregulated the level of anti-inflammatory genes such as Ccl24, Ccr1, IL-11, Cxcl1, Ccl4, Ccl5, Hspb1, TGFb-2 and Mbl2, and was found to be effective against LPSchallenged microglial activation. Rosuvastatin also reduced the phagocytic activity as well as inhibited proliferation and cell adhesion in both unchallenged and LPS-challenged microglia (32). ...
Rosuvastatin, a 3‐hydroxy‐3‐methylglutaryl‐coenzyme (HMG‐CoA) reductase inhibitor, and one of the most popular antihyperlipidemic medications has been found to possess pharmacodynamic activities much different from its usual indication. Recent research studies have revealed the efficacy of rosuvastatin in attenuating neuroinflammation, reducing the progression of Alzheimer's disease, providing protection against cerebral ischemia and spinal cord injury as well as ameliorating epilepsy. Mechanisms behind the neuroprotective potential of rosuvastatin can be attributed to its pleiotropic effects, independent of its ability to inhibit HMG‐CoA reductase. These processes include modulation of several cellular pathways, isoprenylation, effects on oxidative stress, nitrosative levels, inflammation, and immune response. With this review, we aim to assimilate and summarize recent findings on the pharmacological actions of rosuvastatin in attenuating neurological disorders in order to give way for future research in this space.
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... Previously it was recognized as Myc box-dependent-interacting protein 1 which interacts with Myc-box regions of the MYC oncoprotein [173]. The involvement of BIN1 in posterior cortical atrophy has been observed [176]. The relation between the terminal portion of BIN1 and amphiphysin which is a cancer-associated autoantigen, and again to RVS167 which is a popular as a regulator of the cell cycle in yeast is well-establised [173]. ...
Alzheimer's disease (AD) is an irreversible, progressive and neurodegenerative brain disorder characterized by memory impairment that results problems in day-today life and in accomplishing usual tasks, causes inconvenience in understanding visual images and spatial relationships. Familial AD is correlated with the mutations in the amyloid precursor protein (APP) and presenilin genes (PSEN1 and PSEN2) and Aβ metabolism, whereas APOEε4 moderates amyloid-related memory decline in preclinical AD. On the contrary, sporadic AD is found to exist with complex interaction of both genetic and environmental risk factors. Genome-wide association studies and whole-exome and whole-genome sequencing have brought out more than 20 loci correlated with AD risk. Genome-wide associated studies (GWAS) have identified polymorphisms in or near several genes that are correlated with AD risk, including ABCA7, CLU, CR1, CD33, CD2AP, EPHA1, BIN1, PICALM and MS4A. Among most of them, central role of ApoE, CLU and ABCA7 in cholesterol metabolism imposes this pathway in AD pathogenesis. CR1, CD33, MS4A, CLU, ABCA7, EPHA1 and TREM2 are associated with neuroinflammation and dysregulation of the immune response. Genes associated with endocytosis and synaptic function are recognized in several GWAS of LOAD risk, including BIN1, PICALM, CD2AP, EPHA1 and SORL1.
... There is a considerable amount of data which indicate that ABCA7 contributes to AD pathology [12,14,[53][54][55][56][57][58][59], particularly affecting APP processing [14,53] and the phagocytic clearance of A peptides [45,[60][61][62]. Our current study is the first report indicating that ABCA7 alters WAT development. ...
ATP-binding cassette A7 (ABCA7) is a genetic risk factor for late-onset Alzheimer’s disease (AD). It belongs to a group of transporter genes that specializes in regulating lipid transport in the periphery as well as in the brain. ABCA7 has been implicated in a number of roles relating to AD pathology, including phagocytic clearance of amyloid-β peptides. We have discovered that deletion of ABCA7 in mouse causes a dramatic reduction in white adipose tissue (WAT) in female mice. WAT is important in AD context because it is the primary producer of leptin, which is a hormone that is known to modulate AD neuropathology. WAT in male Abca7–/– mice was not altered. The pathological link between ABCA7 and WAT that impacts on AD is unknown. Our transcription analysis revealed that lipin-1 expression was significantly upregulated in female Abca7–/– mice, indicating that ABCA7 affects WAT development. The circulating leptin level was significantly reduced in female Abca7–/– mice without any change in WAT leptin mRNA or protein expression, indicating that ABCA7 does not affect leptin production, but alters the circulating leptin level indirectly by affecting WAT development. Insulin is a key hormone that regulates WAT development, i.e., adipogenesis, and it was significantly reduced in female Abca7–/– mice. These data when put together suggest that ABCA7 plays a role in regulating WAT development and consequently circulating leptin levels, which are known to modulate AD neuropathology.
... In vitro and in vivo experiments have shown ABCA7 pivotal role in phagocytosis and a likely modest role in high-density lipoprotein biogenesis. In Abca7 À/À mice, macrophages and microglia display impaired phagocytosis and clearance of amyloid from the brain, which leads to cognitive impairment (Iwamoto et al., 2006;Tanaka et al., 2011). Therefore, ABCA7, likewise TREM2 and CD33, may play an important role in regulating microglial uptake and clearance of amyloid-beta debris. ...
Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer’s disease (AD).
Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyse the single independent and joint effect of rare and low frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low frequency coding variant (p.G215S, rs72973581, MAF=4.3%) conferring a modest but statistically significant protection against AD (p-value= 6x10-4, OR=0.57, 95% CI 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provide new insights that should address functional studies.
... The in vivo phagocytosis was estimated as described by Tanaka. [21] Briefly LPS was diluted 10-fold with PBS and injected into the mouse peritoneal cavity by 10 µl/g body weight. After overnight starvation the mice were sacrificed and macrophages were recovered from Peritoneal, Liver and Spleen. ...
ABSTRACTCampylobactercoliusually live in the intestinal tract of animals and cause inflammation of the intestine and diarrhea. In this study,C. coliwere isolated from patients having diarrhea and identified based on morphological and biochemical characteristics. Lipopolysaccharide (LPS) is major outer membrane structural component of gram negative bacteriawhichinduces abroad range of biological response.Here,LPS was isolated with hot phenol-water extraction and purifiedby gel filtration using Sephadex G-200. Phagocytosis is essential for fighting infectionsin immune responses to protect organisms from bacteriainvasion hence we studied the effect of purified LPS on phagocytosisboth in vitroandin vivo.The results reported in this study may prove to be valuable in analyzing the LPS effect on host immune response.
(6) EFFECT OF CAMPYLOBACTER COLI LPS ON PHAGOCYTOSIS IN VITRO AND IN VIVO | Request PDF. Available from: https://www.researchgate.net/publication/292374167_EFFECT_OF_CAMPYLOBACTER_COLI_LPS_ON_PHAGOCYTOSIS_IN_VITRO_AND_IN_VIVO [accessed Oct 15 2018].
... LRP1 play roles in the efflux of Aβ from the brain (Ramanathan et al., 2015) and neuronal Aβ uptake and degradation (Kanekiyo et al., 2013). Finally, statins enhance ABCA7-dependent phagocytosis (Tanaka et al., 2011a). Thus, lipid metabolism is involved in modulating Aβ levels. ...
Diabetes is a risk factor for Alzheimer disease (AD). Apolipoprotein E (ApoE) and several genes related to AD have recently been identified by genome-wide association studies (GWAS) as being closely linked to lipid metabolism. Lipid metabolism and glucose-energy metabolism are closely related. Here, we review the emerging evidence regarding the roles of lipid and glucose metabolism in the modulation of β-amyloid, tau, and neurodegeneration during the pathogenesis of AD. Disruption of homeostasis of lipid and glucose metabolism affects production and clearance of β-amyloid and tau phosphorylation, and induces neurodegeneration. A more integrated understanding of the interactions among lipid, glucose, and protein metabolism is required to elucidate the pathogenesis of AD and to develop next-generation therapeutic options.
... Similarly, peritoneal macrophages derived from Abca7 + /hemizygous mice were defective in their capacity to phagocytose apoptotic Jurkat T-cells [13]. In addition, siRNA-mediated knockdown of ABCA7 in BALB/3T3 fibroblasts was shown to inhibit phagocytosis of latex beads by ∼50 % in vitro [14] and in vivo analysis of lung macrophages and peritoneal macrophages in situ showed defective phagocytosis of apoptotic thymocytes and carbon ink particles respectively, in two different strains of ABCA7 deficient mice [13,14,19]. Since there is strong evidence that microglia play a central role in the phagocytic clearance of amyloid-β (Aβ) in the brain [20], we assessed the capacity for bone marrow-derived macrophages derived from Abca7 -/-(Abca7 gene knockout mouse) mice to take up oligomeric Aβ and found that this activity was reduced by 51 % compared with wild type (WT) mice [15]. ...
ATP-binding cassette transporter A7 (ABCA7) is highly expressed in the brain. Recent genome-wide association studies (GWAS) identify ABCA7 single nt polymorphisms (SNPs) that increase Alzheimer's disease (AD) risk. It is now important to understand the true function of ABCA7 in the AD context. We have begun to address this using in vitro and in vivo AD models. Our initial studies showed that transient overexpression of ABCA7 in Chinese hamster ovary cells stably expressing human amyloid precursor protein (APP) resulted in an approximate 50% inhibition in the production of the AD-related amyloid-β (Aβ) peptide as compared with mock-transfected cells. This increased ABCA7 expression was also associated with alterations in other markers of APP processing and an accumulation of cellular APP. To probe for a function of ABCA7 in vivo, we crossed Abca7-/- mice with J20 mice, an amyloidogenic transgenic AD mouse model [B6.Cg-Tg(PDGFBAPPSwInd). 20Lms/J] expressing amutant form of human APP bearing both the Swedish (K670N/M671L) and Indiana (V717F) familial AD mutations. We found that ABCA7 loss doubled insoluble Aβ levels and amyloid plaques in the brain. This did not appear to be related to changes in APP processing (C-terminal fragment analysis), which led us to assess other mechanism by which ABCA7 may modulate Aβ homoeostasis. As we have shown that microglia express high levels of ABCA7, we examined a role for ABCA7 in the phagocytic clearance of Aβ. Our data indicated that the capacity for bone marrow-derived macrophages derived from Abca7-/- mice to phagocytose Aβ was reduced by 51% compared with wild-type (WT) mice. This suggests ABCA7 plays a role in the regulation of Aβ homoeostasis in the brain and that this may be related to Aβ clearance by microglia.
... ABCA7, a member of the ABC transporter superfamily, transports substrates across cell membranes. ABCA7 modulates the C1q complement pathway and affects microglial phagocytosis of apoptotic cells and Aβ [137][138][139]. ABCA7 may also affect cholesterol transfer to ApoE and clearing Aβ aggregates [140,141]. ...
Alzheimer's disease is an important public concern with rising prevalence across the globe. While many therapeutic approaches for Alzheimer's disease have been developed, there are currently no validated disease-modifying treatments. Thus, in order to develop novel treatment strategies, there is a significant need to progress our understanding of the pathogenesis of Alzheimer's disease. Several large genome-wide association studies and whole genome and exome sequencing studies have identified novel genes associated with late-onset Alzheimer's disease. Interestingly, many of the genes are associated with inflammation and the immune system, including complement receptor 1, clusterin, CD33, EPH receptor A1, membrane-spanning 4-domains subfamily A, ATP-binding cassette sub-family A member 7, major histocompatibility complex class II, inositol polyphosphate-5-phosphatase, myocyte enhancer factor 2C, and triggering receptor expressed on myeloid cells 2. The pathogenetic contributions of immune reaction and neuroinflammation in Alzheimer's disease have been regarded largely as part of amyloid cascade hypothesis. The neurotoxic amyloid-β (Aβ) induces activation of immune cells, such as microglia, astrocytes, perivascular macrophages and lymphocytes and decreased capability of clearing Aβ by immune system and chronic inflammation caused by activated immune cells aggravate neuronal damage and eventually Alzheimer's disease. But the precise mechanism and hereditary impact on such process is largely unknown. The current findings in genetic studies suggest that the immunological mechanisms of Alzheimer's disease may extend beyond passive reaction of Aβ, including the development of Alzheimer's disease such as time of onset and rate of progression. In this article, we aimed to review the mechanisms of immune reaction and neuroinflammation in Alzheimer's disease, with an emphasis on the function of genes known to be associated with a risk of Alzheimer's disease in terms of neuroinflammation and immune function.
... ABCA7, a member of the ABC transporter superfamily, transports substrates across cell membranes. ABCA7 modulates the C1q complement pathway and affects microglial phagocytosis of apoptotic cells and Aβ [137][138][139]. ABCA7 may also affect cholesterol transfer to ApoE and clearing Aβ aggregates [140,141]. ...
Yoon SY, Kim YK. The role of immunology and neuroinflammation in genetic predisposition and pathogenesis of Alzheimer’s disease. AIMS Genetics 2015: 2(3): 230 249
... Based on previous studies demonstrating significantly impaired phagocytosis in ABCA7 knock-out mice, it is quite feasible that ABCA7 does play a role in uptake and clearance of aggregated A plaques and aggregates (14,18,46,47). This would be consistent with several other genome-wide association study candidates that have been shown to regulate microglial activity necessary for amyloid removal as opposed to APP processing and trafficking. ...
The ATP-binding cassette transporter A7 (ABCA7) has been identified as a susceptibility factor of late-onset Alzheimer's disease (LOAD) in Genome Wide Association Studies (GWAS). ABCA7 has been shown to mediate phagocytosis and affects membrane trafficking. The current study examines the impact of ABCA7 loss-offunction on amyloid precursor protein (APP) processing and generation of amyloid-β (Aβ). Suppression of endogenous ABCA7 in several different cell lines resulted in increased β-secretase cleavage and elevated Aβ. ABCA7 knockout mice displayed an increased production of endogenous murine amyloid Aβ42 species. Crossing ABCA7 deficient animals to an APP transgenic model resulted in significant increases in the soluble Aβ as compared to mice expressing normal levels of ABCA7. Only modest changes in the amount of insoluble Aβ and amyloid plaque densities were observed once the amyloid pathology was well developed while Aβ deposition was enhanced in younger animals. In vitro studies indicated a more rapid endocytosis of APP in ABCA7 knockout cells that is mechanistically consistent with the increased Aβ production. These in vitro and in vivo findings indicate a direct role of ABCA7 in amyloid processing, which may be associated with its primary biological function to regulate endocytic pathways. Several potential loss-of-function ABCA7 mutations and deletions linked to AD have recently been identified which, in some instances, have a great impact than ApoE allelic variants. A reduction in ABCA7 expression or loss of function would be predicted to increase amyloid production and that may be a contributing factor in the associated AD susceptibility.
Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
... [5][6][7][8][9][10][11][12][13][30][31][32][33] High-sensitivity C-reactive protein levels are reduced by statin therapy, 30 and statins modulate the function of immune cells by downregulating various cell receptors and cytokines involved in inflammation, activating natural killer cells, and enhancing phagocytosis. [31][32][33][34][35] In addition, studies have demonstrated that statins exert direct antibacterial and antiviral effects on pathogenic microorganisms. 12,13,36 The present meta-analysis has several limitations. ...
*These authors contributed equally to this work.A meta-analysis to investigate the association between preoperative statin use and the risk of postoperative infectious complications in patients undergoing surgery.
PubMed® and Embase® databases were searched for relevant studies. Data were extracted using a standardized data collection form. The primary effect measure was the odds ratio (OR) of postoperative infectious complications. Summary OR were calculated.
The analysis included 10 cohort studies with a total of 147 263 participants. Statin use was associated with a lower incidence of postoperative infectious complications in all studies (summary OR 0.917, 95% confidence intervals [CI] 0.862, 0.975, fixed-effects model; summary OR 0.731, 95% CI 0.584, 0.870, random-effects model); cardiac surgery (summary OR 0.673; 95% CI 0.535, 0.847); treatment in the USA (summary OR 0.678; 95% CI 0.597, 0.770); retrospective cohort studies (summary OR 0.664; 95% CI 0.521, 0.846).
Preoperative statin use is associated with a reduced risk of postoperative infectious complications.
© The Author(s) 2015.
... Interestingly, some authors mentioned that statins might induce an increase of VD (61), which appears to be a paradox, because VD synthesis depends on metabolites from the mevalonic acid pathway. However, it appears possible that statin-induced upregulation of the ATP-binding cassette transporter (62), which is also responsible for VD uptake, (63) could explain this phenomenon, in addition to the statin-induced downregulation of the vitamin D degrading enzyme CYP24A1 (17). Although speculative, it could also be possible that an additional pathway for isoprenoid synthesis, which is characteristic for bacteria (64), might have been "imported" by endosymbionts via phagocytosis. ...
The mevalonate pathway provides metabolites for post-translational modifications such as farnesylation, which are critical for the activity of RAS downstream signaling. Subsequently occurring regulatory processes can induce an aberrant stimulation of DNA methyltransferase (DNMT1) as well as changes in histone deacetylases (HDACs) and microRNAs in many cancer cell lines. Inhibitors of the mevalonate pathway are increasingly recognized as anticancer drugs. Extensive evidence indicates an intense cross-talk between signaling pathways, which affect growth, differentiation, and apoptosis either directly or indirectly via epigenetic mechanisms. Herein, we show data obtained by novel transcriptomic and corresponding methylomic or proteomic analyses from cell lines treated with pharmacologic doses of respective inhibitors (i.e., simvastatin, ibandronate). Metabolic pathways and their epigenetic consequences appear to be affected by a changed concentration of NADPH. Moreover, since the mevalonate metabolism is part of a signaling network, including vitamin D metabolism or fatty acid synthesis, the epigenetic activity of associated pathways is also presented. This emphasizes the far-reaching epigenetic impact of metabolic therapies on cancer cells and provides some explanation for clinical observations, which indicate the anticancer activity of statins and bisphosphonates.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
... [12] ...
Drugs (medicines) are considered either the primary therapy or an adjunct to another modality. Physicians of all specialties prescribe drugs on a daily basis, and therefore they need to understand the mode and action by which drugs exert their therapeutic effects. Written records of the use of natural products as medicinal agents date back thousands of years. However, it was not until the early 1800s that the active principles from plants were isolated. Since then thousands of drugs have been introduced to the drugs market. With advances in drug design, molecular biology and genetics, the rate of developing new potent drugs is accelerated. Due to the vast progress in drug development and discovery, medical and pharmacy students, doctors, nurses and pharmacists in training need to learn the principles of therapeutics in order to follow up with the frequent changes in the therapeutics and adapt to them. With contributions from some of my colleagues, this book provides a clear and concise overview of the most important commonly used drugs with emphasis on the pharmacology aspects necessary for a basic understanding of the subject. It reviews the concepts, clinical applications, dosage forms, bioavailability, pharmacokinetics and side effects of a large number of drugs used to alleviate pain, lower cholesterol levels, and treat bacterial infections, diabetes, osteoporosis, bleeding, psoriasis and multiple Sclerosis. This book, with over 750 references, is an excellent pharmacology text for the student who is looking to broaden his/her strengths prior to the exam. The beauty of this text is that it includes essential pharmacology concepts in a compact book that can be quickly referenced and read multiple times during the course of a student's studies. In addition, this guide assists scientists trained in molecular biology, medicinal chemistry and related fields who need to know the basic theories, principles and practical applications of pharmacology. With the addition of pharmacokinetics coverage, ways to improve the bioavailability of commonly used drugs and sections on therapeutics that will help readers identify with diseases and drug treatments, this book provides better preparation of researchers in the basics of pharmacology.
... As statin enhances phagocytosis (Tanaka et al., 2011), an important event necessary for gaining access into the host, macrophages were pretreated with 50 M mevastatin, the classical HMG-CoA reductase inhibitor, followed by L. donovani infection. Mevastatin treatment led to a decrease in PM cholesterol content (36.6%) ( Fig. 2A) and 42.63% inhibition of parasite internalization at 1 h post-infection but 1.67-fold increase in bead uptake (Fig. 2B). ...
Establishment of infection by an intracellular pathogen depends on successful internalization with a concomitant neutralization of host defense machinery. Leishmania donovani, an intramacrophage pathogen, targets host SREBP2, a critical transcription factor, to regulate macrophage plasma membrane cholesterol and mitochondrial reactive oxygen species generation, favouring parasite invasion and persistence. Leishmania infection triggered membrane-raft reorientation-dependent Lyn-PI3K/Akt pathway activation which in turn deactivated GSK3β to stabilize nuclear SREBP2. Moreover, cells perceiving less available intracellular cholesterol due to its sequestration at the plasma membrane resulted in the deregulation of the ER-residing SCAP-SREBP2-Insig circuit thereby assisting increased nuclear translocation of SREBP2. Both increased nuclear transport and stabilization of SREBP2 caused HMGCR-catalyzed cholesterol biosynthesis-mediated plasma membrane cholesterol enrichment leading to decreased membrane-fluidity and plausibly assisting delay in phagosomal acidification. Parasite survival ensuing entry was further ensured by SREBP2-dependent trasnscriptional up-regulation of UCP2, which suppressed mitochondrial ROS generation, one of the primary microbicidal molecules in macrophages recognized for its efficacy against Leishmania. Functional knock-down of SREBP2 both in vitro and in vivo was associated with reduction in macrophage plasma membrane cholesterol, increased ROS production and lower parasite survival. To our knowledge, this study, for the first time, reveals that Leishmania exploits macrophage cholesterol-dependent SREBP2 circuit to facilitate its entry and survival within the host.
... ABCA7 also modulates phagocytosis of apoptotic cells by macrophages via the C1q complement pathway (69). Increasing ABCA7 expression also increases microglial phagocytosis of apoptotic cells, synthetic substrates, and Aβ (67,(69)(70)(71). APP transgenic mice that are ABCA7-deficient have increased Aβ deposition compared to the singly transgenic animals (67). ...
Here, we review the genetic risk factors for late onset Alzheimer’s disease (AD) and their role in AD pathogenesis. Recent advances in our understanding of the human genome, namely technological advances in methods to analyze millions of polymorphisms in thousands of subjects, have revealed new genes associated with AD risk: ABCA7, BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-DBR1, INPP5D, MS4A, MEF2C, NME8, PICALM, PTK2B, SLC24H4-RIN3, SORL1, ZCWPW1. Emerging technologies to analyze the entire genome in large datasets have also revealed coding variants that increase AD risk: PLD3 and TREM2. We review the relationship between these AD risk genes and the cellular and neuropathological features of AD. Together, understanding the mechanisms underlying the association of these genes with risk for disease will provide the most meaningful targets for therapeutic development to-date.
... Phagocytic activity of peritoneal macrophages from ABCA7 knockout mice is decreased as compared to wild-type mice, and induction of phagocytosis by ApoA lipoproteins is dependent on ABCA7 in vivo and in J774 macrophages (Tanaka et al., 2010). A year later, the same laboratory demonstrated that statins induce phagocytosis in an ABCA7dependent manner (Tanaka et al., 2011). Additionally, ABCA7 was found to be involved in response to typhoid fever in children (Khoo et al., 2011). ...
... Kim et al. (2013) showed that ABCA7 inactivation in macrophages reduced phagocytic clearance of Aβ and exaggerated Aβ accumulation in mice. Interestingly, statins are reported to enhance ABCA7dependent phagocytosis through the SREBP pathway (Tanaka et al., 2011a). These studies suggest crosstalk between statins and ABCA7 in Aβ metabolism. ...
The benefits of statins, commonly prescribed for hypercholesterolemia, in treating Alzheimer's disease (AD) have not yet been fully established. A recent randomized clinical trial did not show any therapeutic effects of two statins on cognitive function in AD. Interestingly, however, the results of the Rotterdam study, one of the largest prospective cohort studies, showed reduced risk of AD in statin users. Based on the current understanding of statin actions and AD pathogenesis, it is still worth exploring whether statins can prevent AD when administered decades before the onset of AD or from midlife. This review discusses the possible beneficial effects of statins, drawn from previous clinical observations, pathogenic mechanisms, which include β-amyloid (Aβ) and tau metabolism, genetic and non-genetic risk factors (apolipoprotein E, cholesterol, sex, hypertension, and diabetes), and other clinical features (vascular dysfunction and oxidative and inflammatory stress) of AD. These findings suggest that administration of statins in midlife might prevent AD in late life by modifying genetic and non-genetic risk factors for AD. It should be clarified whether statins inhibit Aβ accumulation, tau pathological features, and brain atrophy in humans. To answer this question, a randomized controlled study using amyloid positron emission tomography (PET), tau-PET, and magnetic resonance imaging would be useful. This clinical evaluation could help us to overcome this devastating disease.
... Indeed, ABCA7 is a homolog of ced-7, the C. elegans gene critical for apoptotic cell engulfment [17]. Here, we note that ectopic ABCA7 expression increases microglial phagocytosis of multiple substrates, including apoptotic cells, Aβ, and synthetic substrates in vitro [17,23,[39][40][41]. Consistent with this possibility, ABCA7 deficient mice have increased Aβ deposition in vivo and rs3764650G in humans has been associated with increased neuritic plaque burden [23,37,38]. ...
Genome-wide association studies (GWAS) have implicated a series of single nucleotide polymorphisms (SNPs) in Alzheimer's disease (AD) risk. Elucidating the function of these SNPs is critical to identifying the underlying pathways and, potentially, novel therapeutic agents. SNPs within the gene ATP binding cassette A7 (ABCA7) reached significance in these studies, warranting investigation into their actions. Here, we analyzed ABCA7 expression in a set of human brain samples as a function of AD-associated SNPs and AD status. We report that the rs3764650T allele that decreases AD risk is associated with increased ABCA7 expression. However, ABCA7 expression is increased in AD individuals. We interpret our findings as suggesting a model wherein increased ABCA7 expression reduces AD risk and that the increased ABCA7 observed in AD reflects an inadequate compensatory change.
In defiance of the vast amount of information regarding Alzheimer's disease (AD) that has been learned over the past thirty years, progress toward developing an effective therapy has been difficult. A neurological ailment that progresses and cannot be reversed is Alzheimer's disease, which shows neurofibrillary tangles, beta-amyloid plaque, and a lack of cognitive processes that is created by tau protein clumps with hyperphosphorylation that finally advances to neuronal damage without a recognized treatment, which has stimulated research into new therapeutic strategies. The protein CAS9 is linked to CRISPR, which is a clustered Regularly Interspaced Short Palindromic Repeat that inactivates or corrects a gene by recognizing a gene sequence that produces a doublestranded break has enchanted a whole amount of interest towards its potency to cure gene sequences in AD. The novel CRISPR-Cas9 applications for developing in vitro and in vivo models to the benefit of AD investigation and therapies are thoroughly analyzed in this work. The discussion will also touch on the creation of delivery methods, which is a significant obstacle to the therapeutic use of CRISPR/Cas9 technology. By concentrating on specific genes, such as those that are significant early-onset AD risk factors and late-onset AD risk factors, like the apolipoprotein E4 (APOE4) gene, this study aims to evaluate the potential application of CRISPR/Cas9 as a possible treatment for AD.
Adenosine triphosphate-binding cassette transporter subfamily A member 7 (ABCA7) is a major risk factor for Alzheimer’s disease. Human neural cell lines were used to investigate the regulation of ABCA7 expression by cholesterol and pro-inflammatory cytokines. Cholesterol was depleted by methyl-β-cyclodextrin, followed by treatment with rosuvastatin to suppress de novo synthesis, while the cells underwent adjustment to low cholesterol. Cholesterol depletion by 50–76% decreased ABCA7 expression by ~40% in C20 microglia and ~21% in A172 astrocytes but had no effect on the protein in SK-N-SH neurons. Cholesterol depletion also suppressed ABCA7 in HMC3 microglia. Previously, cholesterol loss was reported to up-regulate ABCA7 in murine macrophages. ABCA7 was down-regulated during PMA-induced differentiation of human THP-1 monocytes to macrophages. But, cholesterol depletion in THP-1 macrophages by ~71% had no effect on ABCA7. IL-1β and TNFα reduced ABCA7 expression in C20 and HMC3 microglia but not in A172 astrocytes or SK-N-SH neurons. IL-6 did not affect ABCA7 in the neural cells. These findings suggest that ABCA7 is active in regular homeostasis in human neural cells, is regulated by cholesterol in a cell type-dependent manner, i.e., cholesterol depletion down-regulates it in human neuroglia but not neurons, and is incompatible with IL-1β and TNFα inflammatory responses in human microglia.
The pleiotropic benefits of statins may result from their impact on vascular inflammation. The molecular process underlying this phenomenon is not fully elucidated. In the present study, RNA-sequencing designed to investigate gene expression patterns after CD47–SIRPα inhibition identifies a link of statins, efferocytosis and vascular inflammation. In vivo and in vitro studies provide evidence that statins augment programmed cell removal by inhibiting the nuclear translocation of NF-κB1 p50 and suppressing the expression of the critical ‘don’t-eat-me’ molecule, CD47. Statins amplify the phagocytic capacity of macrophages, and thus the anti-atherosclerotic effects of CD47–SIRPα blockade, in an additive manner. Analyses of clinical biobank specimens suggest a similar link between statins and CD47 expression in humans, highlighting the potential translational implications. Taken together, our findings identify efferocytosis and CD47 as pivotal mediators of statin pleiotropy. In turn, statins amplify the anti-atherosclerotic effects of prophagocytic therapies independently of any lipid-lowering effect. Jarr and colleagues show that statins augment efferocytosis by inhibiting the nuclear translocation of NF-κB1 p50 and suppressing the expression of the key ‘don’t-eat-me’ molecule CD47, which in part explains the pleiotropic effects of statins and provides a basis for future translational efforts.
Purpose of review:
Macrophages are key protagonists of atherosclerotic plaque development and hence represent targets of therapeutic intervention. Statins are the most potent widely used atheroprotective drugs. Therefore, whether and how statins influence atheromatous plaque macrophages has remained at the center of cardiovascular research for decades.
Recent findings:
Because statins are capable of regulating macrophage functions in cell culture, largely independent of their cholesterol-lowering effect, it was assumed that these pleiotropic effects operate in vivo as well. Recent experimental data, in line with clinical observations, indicate, however, that statins do not interact with macrophages in atherosclerotic plaques, directly, and instead control their functions and assembly indirectly via changes to circulating lipid levels and endothelial activation.
Summary:
Statin-mediated lipid lowering induces plaque regression which is characterized by a decline in plaque macrophage content. Understanding how statins provoke this protective phenotype may inspire conceptually new therapeutic approaches in cardiovascular medicine.
ATP-binding cassette transporter (ABC) A7 is a membrane protein that belongs to the large family of ABC transporters. It is 54% homologous in amino acid residue sequence to ABCA1 which mediates biogenesis of plasma high density lipoprotein (HDL) from cellular phospholipid and cholesterol with extracellular helical apolipoproteins such as apolipoprotein (apo) A-I. When transfected and expressed, ABCA7 also mediates generation of HDL-like particles but small and of less cholesterol content. However, endogenous ABCA7 is unlikely involved in HDL biogenesis and rather to regulate the host-defense system such as phagocytotic function of the cells. ABCA1 expression is regulated by cellular cholesterol levels, positively by the liver X receptor (LXR) in extrahepatic peripheral cells. However, it is modulated dually in the liver being relevant to transport of cholesterol for its catabolism; positively by LXR and negatively by sterol regulatory element binding protein (SREBP) or hepatic nuclear factor 4α (HNF4α). In contrast, ABCA7 expression was shown to be regulated negatively by the SREBP system so that decrease of cell cholesterol enhances ABCA7 function such as cellular phagocytotic reaction, suggesting that it links cholesterol metabolism to the host defense system. The interest is being build up in ABCA7 as its genomic diversity has been found related to a risk for late-onset Alzheimer's diseases. More recent findings indicate that ABCA7 is involved in metabolism of amyloid β peptide including its phagocytotic clearance. Accordingly, modulation of ABCA7 activity by manipulating cholesterol metabolism may open a new path for management of Alzheimer's disease.
Immunotherapy is revolutionizing the treatment of cancer, and the current immunotherapeutics have remarkably improved the outcomes for some cancer patients. However, we still need answers for patients with immunologically cold tumors that do not benefit from the current immunotherapy treatments. Here, we suggest a novel strategy that is based on using a very old and sophisticated system for cancer immunotherapy, namely "intrinsic cancer vaccination", which seeks to awaken our own immune system to activate tumor-specific T cells. To do this, we must take advantage of the genetic instability of cancer cells and the expression of cancer cell neoantigens to trigger immunity against cancer cells. It will be necessary to not only enhance the phagocytosis of cancer cells by antigen presenting cells but also induce immunogenic cancer cell death and the subsequent immunogenic clearance, cross-priming and generation of tumor-specific T cells. This strategy will allow us to avoid using known tumor-specific antigens, ex vivo manipulation or adoptive cell therapy; rather, we will efficiently present cancer cell neoantigens to our immune system and propagate the cancer-immunity cycle. This strategy simply follows the natural cycle of cancer-immunity from its very first step, and therefore could be combined with any other treatment modality to yield enhanced efficacy.
This chapter discusses the current understanding of research into the genetics that underpins the two major neurodegenerative disease, Alzheimer's disease (AD) and Parkinson's disease (PD). It first reviews the established genetic loci for early‐onset familial AD (EOFAD), focusing on autosomal dominant AD (ADAD), as well as genetic loci implicated as genetic risk factors for late‐onset AD (LOAD) through large‐scale genome‐wide association studies (GWAS), with a particular emphasis on classifying the latter by biological pathways. Then , it reviews genetic loci associated with both monogenic and late‐onset sporadic forms of PD. Genetic studies of neurodegenerative disease such as AD and PD have provided the research field with a more comprehensive understanding of the genetic basis of each disease and concurrently a greater understanding of biological pathways involved in disease pathogenesis. The latter holds the key to the eventual development of treatments for both diseases.
La maladie d’Alzheimer (MA) se caractérise par une perte mnésique progressive. La quantité de cholestérol est plus élevée dans les cerveaux de patients atteints de la MA. De plus, l’existence d’un site de liaison entre le cholestérol (SLC) et l’Amyloid Precursor Protein (APP) a été démontrée par résonance magnétique nucléaire. Les mutations effectuées dans le SLC de l’APP abolissent totalement l’interaction entre les peptides et des liposomes chargés en cholestérol. Tous les mutants du SLC produisent beaucoup moins d’Aβ40 et Aβ42 sans modifier les produits de clivage de l’APP. Nous avons mis en évidence deux catégories de mutations : les mutations juxtamembranaires qui augmentent la sécrétion de fragments courts d’Aβ et les mutations transmembranaires, incluant la mutation familiale italienne, qui diminuent la sécrétion de peptides courts d’Aβ. Ces résultats suggèrent un décalage du clivage des mutants par la γ-sécrétase et/ou une modification de sa processivité conduisant à la formation de peptides de courtes tailles. Parallèlement, nous avons montré que des cultures primaires de neurones exprimant l’ApoE4 sécrètent en plus grande quantité les peptides amyloïdes Aβ38, 40 et 42 comparé à des neurones exprimant l’ApoE3. Les neurones ApoE4 expriment plus fortement les protéines tau et phospho-tau, mais plus faiblement l’ApoE « full lenght » par rapport aux neurones ApoE3. Le SLC et le génotype ApoE4 contribuent donc à l’augmentation de la sécrétion de peptides amyloïdes. Il serait intéressant de connaître les mécanismes cellulaires impliquant le SLC de l’APP, le cholestérol et son transporteur l’ApoE.
Cholesterol export from cells to extracellular acceptors represents the first step of the reverse cholesterol transport process and is an essential part of the multifaceted pathway for cells to control their cholesterol levels. Malfunction of this pathway leads to cholesterol accumulation in cells such as macrophages, which can form the basis of conditions like atherosclerosis. A number of ATP-binding cassette (ABC) transporters, namely ABCA1, ABCA7, ABCG1, and ABCG4, play an essential role in this process. In this chapter, we describe methods utilizing radiolabeled sterols for measuring ABC-transporter mediated sterol export, utilizing endogenously expressed transporters as well as overexpression systems.
ABCA7 is a member of the ATP binding cassette transporter gene superfamily. These multispan transmembrane proteins are highly conserved and exist in organisms from bacteria to humans. Energy derived from the hydrolysis of ATP is used to transport a number of substrates across both the cellular and intracellular lipid membranes.
Apolipoprotein-dependent cholesterol efflux, sterol homeostasis and lipid metabolism can all be attributed to ABCA proteins to some degree, but how these roles manifest within the CNS and BBB is relatively unknown. Putative functionality within Alzheimer’s disease has been suggested for ABCA7 based on ABCA1 functionality and the observed homology between the proteins. Whilst cholesterol efflux is a minor role for ABCA7 there is a suggestion any reduction could hinder APOE lipidation. As lipidated APOE in the brain reduces Aβ accumulation, any inhibitor to this APOE lipidation could increase Aβ levels.
ABCA7 is a molecule with high homology to ABCA1, an essential protein for the generation of HDL. However, although exogenously transfected ABCA7 supports the generation of HDL, endogenous ABCA7 does not mediate this reaction. ABCA7 is regulated by sterol regulatory element-binding protein 2 whereby ABCA7 expression responds inversely to cellular sterol levels of ABCA1, indicating it has functions other than the elimination of cellular cholesterol. In fact, ABCA7 is strongly associated with phagocytosis of various targets, including microorganisms and apoptotic cells. Accordingly, helical apolipoproteins and statins enhance phagocytic activity through increasing ABCA7, by stabilizing it and by activating sterol regulatory element-binding protein 2. Recent genome-wide association studies identified single nucleotide polymorphisms of ABCA7 as risk factors of Alzheimer's disease and schizophrenia. While physiological roles of ABCA7 are not completely understood and the grounds for the genome-wide association studies findings are also unknown, ABCA7 has become a focus of keen interest.
Low levels of circulating HDL cholesterol (HDL-C) is an independent cardiovascular risk factor. However, whether increases in HDL-C levels protect against cardiovascular disease remains unclear. This review proposes that HMG-CoA reductase inhibitors (statins) increase HDL-C levels through the production of small and lipid-poor nascent HDL/apoA-I. Statins seem to upregulate apoA-I synthesis, leading to an increase in HDL particle number and inhibition of CETP, which results in increased HDL particle size. Pitavastatin causes a greater rise in blood HDL-C levels with more efficacious production of apoA-I compared with other statins such as atorvastatin, pravastatin, simvastatin and rosuvastatin, and has relatively low inhibitory action on CETP. This article reviews the potential role of pitavastatin in HDL therapy.
Infectious complications of cardiac surgery are often severe and life threatening. Statins having both immunomodulatory and anti-inflammatory effects were intuitively thought to influence the development of postsurgical infections. We sought to systematically examine whether any association exists between statin use and risk of infectious complications in patients undergoing cardiac surgery. We searched Ovid MEDLINE, Ovid EMBASE, Thomson Scientific Web of Science, and Elsevier Scopus from inception through February 2011 for comparative studies examining the association between statin use and risk of postoperative infections in patients undergoing cardiac surgery. We contacted a study's author for missing information. We conducted a random-effects meta-analysis of individual studies' odds ratios (adjusted for potential confounders). We identified 6 cohort studies for inclusion, 3 of which were conducted in Canada and 3 of which were conducted in the United States. Four were single-center studies, and 2 were population based. Exposure ascertainment was based on a review of admission medication list or prescription databases. Infectious outcomes were heterogeneous and included surgical site infections within 30 days, serious infections (sepsis), or any other postoperative infection. Statin use in the preoperative period was associated with a trend toward reduction in the incidence of postoperative infections in patients who underwent cardiac surgery (odds ratio, 0.81 [95% confidence interval, 0.64-1.01]; P=.06 I-2=75%). Heterogeneity was explained by country effect. Studies performed in Canada showed weaker associations than studies performed in the United States. This difference could not be attributed to study quality alone. We did not find good evidence to support an association between statin use and postoperative infectious complications. However, the trend toward statistical significance for this association indicates that further investigation is warranted.
Death of vascular smooth muscle cells (VSMCs) has been demonstrated in vessel development and in disease, most notably in atherosclerosis, but also after injury and remodelling. VSMC death promotes multiple features of vulnerable plaques, but also induces features of normal vessel ageing and cystic medial necrosis, including loss of VSMCs, elastin fragmentation and loss, increased glycosaminoglycans and speckled calcification. VSMC apoptosis in the absence of efficient phagocytosis also produces inflammation due to secondary necrosis; in contrast, VSMC apoptosis in normal vessels can be silent. We have investigated the consequences of VSMC apoptosis in both disease and during vessel remodelling. We find that VSMCs release specific cytokines dependent upon the mode of cell death; IL-1β predominates during apoptosis, whilst IL-1α predominates during necrosis. Both IL-1α and β promote release of further cytokines from adjacent live cells, in particular IL-6 and MCP-1. The balance of cytokines results in pathology with differing compositions, including inflammation or neointima formation/vascular repair, via direct promotion of VSMC proliferation and migration. Thus, VSMC death can promote either pathology or repair, depending upon the context and cytokine signalling.
ATP-binding-cassette transporter 1 (ABC1) has been implicated in processes related to membrane-lipid turnover. Here, using in vivo loss-of-function and in vitro gain-of-function models, we show that ABC1 promotes Ca2+-induced exposure of phosphatidylserine at the membrane, as determined by a prothrombinase assay, membrane microvesiculation and measurement of transbilayer redistribution of spin-labelled phospholipids. That ABC1 promotes engulfment of dead cells is shown by the impaired ability of ABC1-deficient macrophages to engulf apoptotic preys and by the acquisition of phagocytic behaviour by ABC1 transfectants. Release of membrane phospholipids and cholesterol to apo-AI, the protein core of the cholesterol-shuttling high-density lipoprotein (HDL) particle, is also ABC1-dependent. We propose that both the efficiency of apoptotic-cell engulfment and the efflux of cellular lipids depend on ABC1-induced perturbation of membrane phosphatidylserine turnover. Transient local exposure of anionic phospholipids in the outer membrane leaflet may be sufficient to alter the general properties of the membrane and thus influence discrete physiological functions.
We previously reported that the endogenous ATP-binding cassette transporter (ABC)A7 strongly associates with phagocytic function rather than biogenesis of high-density lipoprotein (HDL), being regulated by sterol-regulatory element binding protein (SREBP)2. Phagocytic activity was found enhanced by apolipoprotein (apo)A-I and apoA-II more than twice the maximum in J774 and mouse peritoneal macrophages. Therefore we investigated the molecular basis of this reaction in association with the function of ABCA7. Similar to ABCA1, ABCA7 was degraded, likely by calpain, and apoA-I and apoA-II stabilize ABCA7 against degradation. Cell surface biotinylation experiments demonstrated that endogenous ABCA7 predominantly resides on the cell surface and that the apolipoproteins increase the surface ABCA7. The increase of phagocytosis by apolipoproteins was retained in the J774 cells treated with ABCA1 siRNA and in the peritoneal macrophages from ABCA1-knockout mice, but it was abolished in the J774 cells treated with ABCA7 siRNA and in the peritoneal macrophages from ABCA7-knockout mice. Phagocytosis was decreased in the cells in the peritoneal cavity of the ABCA7-knockout mouse compared with the wild-type control. We thus concluded that extracellular helical apolipoproteins augment ABCA7-associated phagocytosis by stabilizing ABCA7. The results demonstrated direct enhancement of the host defense system by HDL components.
Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease.
We randomly assigned 6595 men, 45 to 64 years of age, with a mean (+/- SD) plasma cholesterol level of 272 +/- 23 mg per deciliter (7.0 +/- 0.6 mmol per liter) to receive pravastatin (40 mg each evening) or placebo. The average follow-up period was 4.9 years. Medical records, electrocardiographic recordings, and the national death registry were used to determine the clinical end points.
Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definite coronary events (specified as nonfatal myocardial infarction or death from coronary heart disease) in the placebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent; 95 percent confidence interval, 17 to 43 percent; P < 0.001). There were similar reductions in the risk of definite nonfatal myocardial infarctions (31 percent reduction, P < 0.001), death from coronary heart disease (definite cases alone: 28 percent reduction, P = 0.13; definite plus suspected cases: 33 percent reduction, P = 0.042), and death from all cardiovascular causes (32 percent reduction, P = 0.033). There was no excess of deaths from noncardiovascular causes in the pravastatin group. We observed a 22 percent reduction in the risk of death from any cause in the pravastatin group (95 percent confidence interval, 0 to 40 percent; P = 0.051).
Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarction.
This study explores the role of mevalonate inhibitors in the activation of NF-kbeta and the induction of inducible nitric oxide synthase (iNOS) and cytokines (TNF-alpha, IL-1beta, and IL-6) in rat primary astrocytes, microglia, and macrophages. Lovastatin and sodium phenylacetate (NaPA) were found to inhibit LPS- and cytokine-mediated production of NO and expression of iNOS in rat primary astrocytes; this inhibition was not due to depletion of end products of mevalonate pathway (e.g., cholesterol and ubiquinone). Reversal of the inhibitory effect of lovastatin on LPS-induced iNOS expression by mevalonate and farnesyl pyrophosphate and reversal of the inhibitory effect of NaPA on LPS-induced iNOS expression by farnesyl pyrophosphate, however, suggests a role of farnesylation in the LPS-mediated induction of iNOS. The inhibition of LPS-mediated induction of iNOS by FPT inhibitor II, an inhibitor of Ras farnesyl protein transferase, suggests that farnesylation of p21(ras) or other proteins regulates the induction of iNOS. Inhibition of LPS-mediated activation of NF-kbeta by lovastatin, NaPA, and FPT inhibitor II in astrocytes indicates that the observed inhibition of iNOS expression is mediated via inhibition of NF-kbeta activation. In addition to iNOS, lovastatin and NaPA also inhibited LPS-induced expression of TNF-alpha, IL-1beta, and IL-6 in rat primary astrocytes, microglia, and macrophages. This study delineates a novel role of the mevalonate pathway in controlling the expression of iNOS and different cytokines in rat astrocytes, microglia, and macrophages that may be important in developing therapeutics against cytokine- and NO-mediated neurodegenerative diseases.
Tangier disease (TD) was first discovered nearly 40 years ago in two siblings living on Tangier Island. This autosomal co-dominant condition is characterized in the homozygous state by the absence of HDL-cholesterol (HDL-C) from plasma, hepatosplenomegaly, peripheral neuropathy and frequently premature coronary artery disease (CAD). In heterozygotes, HDL-C levels are about one-half those of normal individuals. Impaired cholesterol efflux from macrophages leads to the presence of foam cells throughout the body, which may explain the increased risk of coronary heart disease in some TD families. We report here refining of our previous linkage of the TD gene to a 1-cM region between markers D9S271 and D9S1866 on chromosome 9q31, in which we found the gene encoding human ATP cassette-binding transporter 1 (ABC1). We also found a change in ABC1 expression level on cholesterol loading of phorbol ester-treated THP1 macrophages, substantiating the role of ABC1 in cholesterol efflux. We cloned the full-length cDNA and sequenced the gene in two unrelated families with four TD homozygotes. In the first pedigree, a 1-bp deletion in exon 13, resulting in truncation of the predicted protein to approximately one-fourth of its normal size, co-segregated with the disease phenotype. An in-frame insertion-deletion in exon 12 was found in the second family. Our findings indicate that defects in ABC1, encoding a member of the ABC transporter superfamily, are the cause of TD.
Endothelial cell adhesion molecules (CAMs) E-selectin, ICAM-1, and VCAM-1 play variably important roles in immune-mediated processes. They are induced by the proinflammatory cytokines IL-1 and TNF-alpha, and NF-kappaB is required for the regulated expression of all three genes. Regulators of this pathway could potentially be potent immune modulators. We studied the effect of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, simvastatin, on cytokine-induced expression of CAMs in HUVEC. Unexpectedly, pretreatment with simvastatin potentiated the induction of all three endothelial CAMs by IL-1 and TNF, but not LPS or PMA, as detected by flow cytometry. Northern blot analysis demonstrated an increase in steady state IL-1-induced E-selectin mRNA levels in cells pretreated with simvastatin. This was associated with an increase in nuclear translocation of NF-kappaB, as detected by EMSA. The effect of simvastatin was reversed by mevalonate and geranylgeranyl pyrophosphate but not squalene, indicating that an inhibitory prenylated protein is involved in endothelial responses to proinflammatory cytokines. Pertussis toxin mimicked the effect of simvastatin, and the G protein activator NaF inhibited the cytokine-induced expression of endothelial CAMs, indicating that a Gialpha protein is involved. These results demonstrate that cytokine-mediated activation of the endothelium, and specifically CAM induction, can be modulated by a heterotrimeric G protein-coupled pathway. This may represent a "basal tone" of endothelial inactivation, which can either be disinhibited or amplified, depending on the stimulus.
Murine macrophage RAW264 were investigated for their response to lipid-free apolipoproteins. Preincubation of the cells with 300 microM dibutyryl cyclic (dBc) AMP for 16 h induced specific binding of apolipoprotein (apo) A-I to the cells and apoA-I-mediated HDL formation with cellular lipids, neither of which was detected in the absence of dBcAMP. Dose-dependent changes of the apoA-I specific binding and the apoA-I-mediated cholesterol release were largely superimposable. ApoA-II also mediated lipid release after the treatment of the cells with dBcAMP and effectively displaced the apoA-I binding to the cells. In contrast, cellular cholesterol efflux to lipid microemulsion and to 2-(hydroxypropyl)-beta-cyclodextrin was uninfluenced by the dBcAMP treatment. To induce the cellular reactivity with apoA-I, the incubation with dBcAMP required at least 6 h. Actinomycin D, cycloheximide, puromycin, and brefeldin A suppressed both the induction of apoA-I-mediated lipid release and the apoA-I specific binding to the cells. Analysis of the expression level of ABC1 mRNA by using reverse transcription-polymerase chain reaction and oligonucleotide arrays revealed that ABC1 mRNA was already expressed in the dBcAMP-untreated cells, and the dBcAMP treatment for 16 h enhanced its expression 9-13-fold. We conclude that dBcAMP selectively induces apolipoprotein-mediated cellular lipid release and accordingly high-density lipoprotein generation by inducing specific binding of apolipoprotein, but does not influence diffusion-mediated lipid efflux. The cell-apolipoprotein interaction seems to depend on cellular protein biosynthesis and transport. A substantial increase in the level of ABC1 mRNA caused by the dBcAMP treatment indicates that ATP-binding cassette transporter 1, the protein product of ABC1, may directly be responsible for the interaction, but the question about the absence of the interaction with its baseline expression level remains.
LXR alpha is a nuclear receptor that has previously been shown to regulate the metabolic conversion of cholesterol to bile acids. Here we define a role for this transcription factor in the control of cellular cholesterol efflux. We demonstrate that retroviral expression of LXR alpha in NIH 3T3 fibroblasts or RAW264.7 macrophages and/or treatment of these cells with oxysterol ligands of LXR results in 7- to 30-fold induction of the mRNA encoding the putative cholesterol/phospholipid transporter ATP-binding cassette (ABC)A1. In contrast, induction of ABCA1 mRNA in response to oxysterols is attenuated in cells that constitutively express dominant-negative forms of LXR alpha or LXR beta that lack the AF2 transcriptional activation domain. We further demonstrate that expression of LXR alpha in NIH 3T3 fibroblasts and/or treatment of these cells with oxysterols is sufficient to stimulate cholesterol efflux to extracellular apolipoprotein AI. The ability of oxysterol ligands of LXR to stimulate efflux is dramatically reduced in Tangier fibroblasts, which carry a loss of function mutation in the ABCA1 gene. Taken together, these results indicate that cellular cholesterol efflux is controlled, at least in part, at the level of transcription by a nuclear receptor-signaling pathway. They suggest a model in which activation of LXRs by oxysterols in response to cellular sterol loading leads to induction of the ABCA1 transporter and the stimulation of lipid efflux to extracellular acceptors. These findings have important implications for our understanding of mammalian cholesterol homeostasis and suggest new opportunities for pharmacological regulation of cellular lipid metabolism.
Patients experience the highest rate of death and recurrent ischemic events during the early period after an acute coronary syndrome, but it is not known whether early initiation of treatment with a statin can reduce the occurrence of these early events.
To determine whether treatment with atorvastatin, 80 mg/d, initiated 24 to 96 hours after an acute coronary syndrome, reduces death and nonfatal ischemic events.
A randomized, double-blind trial conducted from May 1997 to September 1999, with follow-up through 16 weeks at 122 clinical centers in Europe, North America, South Africa, and Australasia.
A total of 3086 adults aged 18 years or older with unstable angina or non-Q-wave acute myocardial infarction.
Patients were stratified by center and randomly assigned to receive treatment with atorvastatin (80 mg/d) or matching placebo between 24 and 96 hours after hospital admission.
Primary end point event defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency rehospitalization.
A primary end point event occurred in 228 patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the placebo group (relative risk [RR], 0.84; 95% confidence interval [CI], 0.70-1.00; P =.048). There were no significant differences in risk of death, nonfatal myocardial infarction, or cardiac arrest between the atorvastatin group and the placebo group, although the atorvastatin group had a lower risk of symptomatic ischemia with objective evidence and requiring emergency rehospitalization (6.2% vs 8.4%; RR, 0.74; 95% CI, 0.57-0.95; P =.02). Likewise, there were no significant differences between the atorvastatin group and the placebo group in the incidence of secondary outcomes of coronary revascularization procedures, worsening heart failure, or worsening angina, although there were fewer strokes in the atorvastatin group than in the placebo group (12 vs 24 events; P =.045). In the atorvastatin group, mean low-density lipoprotein cholesterol level declined from 124 mg/dL (3.2 mmol/L) to 72 mg/dL (1.9 mmol/L). Abnormal liver transaminases (>3 times upper limit of normal) were more common in the atorvastatin group than in the placebo group (2.5% vs 0.6%; P<.001).
For patients with acute coronary syndrome, lipid-lowering therapy with atorvastatin, 80 mg/d, reduces recurrent ischemic events in the first 16 weeks, mostly recurrent symptomatic ischemia requiring rehospitalization.
The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial showed that pravastatin significantly reduced mortality and coronary heart disease (CHD) events in 9014 patients with known CHD and total cholesterol 4.0 to 7.0 mmol/L at baseline. Secondary objectives included assessment of CHD event reduction according to lipid levels.
We investigated the relationships of baseline and on-study lipids with subsequent CHD events in separate Cox models. Treatment effect on CHD event reduction was examined by baseline lipids and after adjustment for on-study lipid levels. Baseline lipids were significant predictors of CHD events. The adjusted relative risk per mmol/L (on placebo) was 1.24 (P=0.004) for total cholesterol, 1.28 (P=0.002) for low-density lipoprotein cholesterol, and 0.52 (P=0.004) for high-density lipoprotein cholesterol. Apolipoproteins A1 and B were strong predictors (each P=0.001). Pravastatin reduced the risk of the composite outcome of fatal CHD or nonfatal myocardial infarction by 24% (95% confidence interval [CI], 15% to 32%) and the expanded end point of fatal CHD, nonfatal myocardial infarction, unstable angina, or coronary revascularization by 17% (95% CI, 10% to 24%). Similar relative effects were observed for different categories of baseline lipids. The proportion of treatment effect explained by on-study lipid levels was 67% (95% CI, 27% to 106%) for the composite and 97% (95% CI, 49% to 145%) for the expanded end point. The most important lipids associated with event reduction were apolipoprotein B, low-density lipoprotein cholesterol, and the combination of total and high-density lipoprotein cholesterol.
Changes in lipid levels can explain all or most of the observed benefit of pravastatin. Some treatment effect may also be mediated through nonlipid changes.
The ATP-binding cassette transporter A1 (ABCA1) facilitates the cellular release of cholesterol and choline-phospholipids to apolipoprotein A-I (apoA-I) and several studies indicate that vesicular transport is associated with ABCA1 function. Syntaxins play a major role in vesicular fusion and have also been demonstrated to interact with members of the ABC-transporter family. Therefore, we focused on the identification of syntaxins that directly interact with ABCA1. The expression of syntaxins and ABCA1 in cultured human monocytes during M-CSF differentiation and cholesterol loading was investigated and syntaxins 3, 6, and 13 were found induced in foam cells together with ABCA1. Immunoprecipitation experiments revealed a direct association of syntaxin 13 and full-length ABCA1, whereas syntaxin 3 and 6 failed to interact with ABCA1. The colocalization of ABCA1 and syntaxin 13 was also shown by immunofluorescence microscopy. Silencing of syntaxin 13 by small interfering RNA (siRNA) led to reduced ABCA1 protein levels and hence to a significant decrease in apoA-I-dependent choline-phospholipid efflux. ABCA1 is localized in Lubrol WX-insoluble raft microdomains in macrophages and syntaxin 13 and flotillin-1 were also detected in these detergent resistant microdomains along with ABCA1. Syntaxin 13, flotillin-1, and ABCA1 were identified as phagosomal proteins, indicating the involvement of the phagosomal compartment in ABCA1-mediated lipid efflux. In addition, the uptake of latex phagobeads by fibroblasts with mutated ABCA1 was enhanced when compared with control cells and the recombinant expression of functional ABCA1 normalized the phagocytosis rate in Tangier fibroblasts. It is concluded that ABCA1 forms a complex with syntaxin 13 and flotillin-1, residing at the plasma membrane and in phagosomes that are partially located in raft microdomains.
ABCA7 is homologous to ABCA1 and has recently been shown in cell culture to bind apolipoprotein A-I (apoA-I) and to promote the efflux of phospholipids. However, it is not known if ABCA7 promotes lipid efflux in vivo. When expressed in HEK293 cells, both human and mouse ABCA7 promoted phospholipid efflux to apoA-I but no detectable cholesterol efflux. However, genetic knockdown of ABCA7 in mouse peritoneal macrophages did not affect phospholipid or cholesterol efflux to apoA-I. Moreover, in ABCA1-knockout macrophages, there was no detectable apoA-I-stimulated phospholipid efflux, inconsistent with a residual role of ABCA7. In contrast to plasma membrane localization of ABCA7 in transfected embryonic kidney cells, immunofluorescence microscopy of endogenous ABCA7 in macrophages showed a predominantly intracellular localization of the protein. Strikingly, immunofluorescence studies of adult mouse kidney revealed an apical brush border membrane localization of ABCA7 in the proximal tubule, suggesting that ABCA7 may come in contact with apoA-I in the glomerular filtrate.
Although ABCA7 does not contribute to apolipoprotein-mediated lipid efflux in resting macrophages, its cell surface location in the kidney suggests that it could serve such a role in tissue microenvironments.
Mutations in the A class of ATP-binding cassette transporters (ABCA) are causally implicated in three human diseases: Tangier disease (ABCA1), Stargadt's macular degeneration (ABCA4), and neonatal respiratory failure (ABCA3). Both ABCA1 and ABCA4 have been shown to transport lipids across cellular membranes, and ABCA3 may play a similar role in transporting pulmonary surfactant. Although the functions of the other 10 ABCA class transporters identified in the human genome remain obscure, ABCA7-transfected cells have been shown to efflux lipids in response to stimulation by apolipoprotein A-I. In an effort to elucidate the physiologic role of ABCA7, we generated mice lacking this transporter (Abca7-/- mice). Homozygous null mice were produced from intercrosses of heterozygous null mice at the expected Mendelian frequency and developed normally without any obvious phenotypic abnormalities. Cholesterol and phospholipid efflux stimulated by apolipoprotein A-I from macrophages isolated from wild type and Abca7-/- mice did not differ, suggesting that these activities may not be central to the physiological role of the transporter in vivo. Abca7-/- females, but not males, had significantly less visceral fat and lower total serum and high density lipoprotein cholesterol levels than wild type, gender-matched littermates. ABCA7 expression was detected in hippocampal and cortical neurons by in situ hybridization and in brain and white adipose tissue by Western blotting. Induction of adipocyte differentiation from 3T3 fibroblasts in culture led to a marked increase in ABCA7 expression. These studies suggest that ABCA7 plays a novel role in lipid and fat metabolism that Abca7-/- mice can be used to elucidate.
Statins are potent, cholesterol-lowering agents with newly appreciated, broad anti-inflammatory properties, largely based upon their ability to block the prenylation of Rho GTPases, including RhoA. Because phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, which is inhibited by RhoA, we sought to determine whether statins enhanced efferocytosis. The effect of lovastatin on efferocytosis was investigated in primary human macrophages, in the murine lung, and in human alveolar macrophages taken from patients with chronic obstructive pulmonary disease. In this study, we show that lovastatin increased efferocytosis in vitro in an 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase-dependent manner. Lovastatin acted by inhibiting both geranylgeranylation and farnesylation, and not by altering expression of key uptake receptors or by increasing binding of apoptotic cells to phagocytes. Lovastatin appeared to exert its positive effect on efferocytosis by inhibiting RhoA, because it 1) decreased membrane localization of RhoA, to a greater extent than Rac-1, and 2) prevented impaired efferocytosis by lysophosphatidic acid, a potent inducer of RhoA. Finally, lovastatin increased efferocytosis in the naive murine lung and ex vivo in chronic obstructive pulmonary disease alveolar macrophages in an HMG-CoA reductase-dependent manner. These findings indicate that statins enhance efferocytosis in vitro and in vivo, and suggest that they may play an important therapeutic role in diseases where efferocytosis is impaired and inflammation is dysregulated.
ABCA7 is highly homologous to ABCA1 and mediates cellular cholesterol and phospholipid release by apolipoproteins when transfected in vitro. However, expression of ABCA7 was downregulated by increased cellular cholesterol while ABCA1 was upregulated, and the results were consistent by forced expression or downregulation of sterol-responsive/regulatory element (SRE) binding proteins (SREBPs). We analyzed the promoter of the ABCA7 gene and identified the new exon encoding 96 bp (mouse) and 95 bp (human) of the 5' untranslated region and the transcription start site at 1,122 bp (mouse) and 1,260 bp (human) upstream of the initiation methionine codon. At 5' upstream of this exon is the ABCA7 proximal promoter containing multiple binding sites of transcription factors for hematopoiesis and SRE of 9 bp at 212 bp (mouse) and 179 bp (human) upstream of the new exon. The apolipoprotein A-I-mediated lipid release was not influenced by suppression of the endogenous ABCA7 with small interfering RNA in mouse fibroblasts or by its increase in ABCA1-deficient mouse cells. In contrast, phagocytic activity was altered in parallel to the ABCA7 expression in these cells. When phagocytosis was induced, the messages increased for SREBP2, ABCA7, and other SREBP2-regulated proteins. The ABCA1 message decreased in this condition. We conclude that the ABCA7 gene is regulated by sterol in the opposite direction to ABCA1 through SRE/SREBP2 and that expression of ABCA7 by this regulation is associated with phagocytic activity.
The mammalian ATP-binding cassette transporters A1 and A7 (ABCA1 and -A7) show sequence similarity to CED-7, a Caenorhabditis elegans gene that mediates the clearance of apoptotic cells. Using RNA interference or gene targeting, we show that knock down of macrophage ABCA7 but not -A1 results in defective engulfment of apoptotic cells. In response to apoptotic cells, ABCA7 moves to the macrophage cell surface and colocalizes with the low-density lipoprotein receptor-related protein 1 (LRP1) in phagocytic cups. The cell surface localization of ABCA7 and LRP1 is defective in ABCA7-deficient cells. C1q is an opsonin of apoptotic cells that acts via phagocyte LRP1 to induce extracellular signal-regulated kinase (ERK) signaling. We show that ERK signaling is required for phagocytosis of apoptotic cells and that ERK phosphorylation in response to apoptotic cells or C1q is defective in ABCA7-deficient cells. These studies reveal a major role of ABCA7 and not -A1 in the clearance of apoptotic cells and therefore suggest that ABCA7 is an authentic orthologue of CED-7.
The involvement of the RAS superfamily of monomeric GTPases in carcinogenesis is increasingly being appreciated. A complex array of post-translational modifications and a highly sophisticated protein network regulate the spatio-temporal activation of these GTPases. Previous attempts to pharmacologically target this family have focused on the development of farnesyltransferase inhibitors, but the performance of such agents in cancer clinical trials has not been as good as hoped. Here, we review emerging druggable targets and novel therapeutic approaches targeting prenylation and post-prenylation modifications and the functional regulation of GDP/GTP exchange as exciting alternatives for anticancer therapy.
The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), a multicenter, randomized, double-blind study, tested the efficacy of cholesterol lowering in reducing risk of coronary heart disease (CHD) in 3,806 asymptomatic middle-aged men with primary hypercholesterolemia (type II hyperlipoproteinemia). The treatment group received the bile acid sequestrant cholestyramine resin and the control group received a placebo for an average of 7.4 years. Both groups followed a moderate cholesterol-lowering diet. The cholestyramine group experienced average plasma total and low-density lipoprotein cholesterol (LDL-C) reductions of 13.4% and 20.3%, respectively, which were 8.5% and 12.6% greater reductions than those obtained in the placebo group. The cholestyramine group experienced a 19% reduction in risk (P<.05) of the primary end point—definite CHD death and/or definite nonfatal myocardial infarction—reflecting a 24% reduction in definite CHD death and a 19% reduction in nonfatal myocardial infarction. The cumulative seven-year incidence of the primary end point was 7% in the cholestyramine group v8.6% in the placebo group. In addition, the incidence rates for new positive exercise tests, angina, and coronary bypass surgery were reduced by 25%, 20%, and 21%, respectively, in the cholestyramine group. The risk of death from all causes was only slightly and not significantly reduced in the cholestyramine group. The magnitude of this decrease (7%) was less than for CHD end points because of a greater number of violent and accidental deaths in the cholestyramine group. The LRC-CPPT findings show that reducing total cholesterol by lowering LDL-C levels can diminish the incidence of CHD morbidity and mortality in men at high risk for CHD because of raised LDL-C levels. This clinical trial provides strong evidence for a causal role for these lipids in the pathogenesis of CHD.
HMG-CoA reductase, in addition to being the rate-limiting enzyme in the cholesterol biosynthetic pathway, is involved in the regulation of receptors for low-density lipoprotein (LDL)-cholesterol. Clinical studies in men and women demonstrate that inhibitors of HMG-CoA reductase (statins), by reducing plasma cholesterol, may limit the development of atherosclerosis and reduce the risk of mortality and ischemic events. Preclinical evidence suggests that under controlled conditions of plasma cholesterol lowering, statins may have ancillary properties or pleiotropic effects, which may directly limit atherosclerosis progression. In this review, pleiotropic effects have been defined as 'ancillary properties of statins, which result in hepatic and/or vascular changes that may or may not be a consequence of inhibition of HMG-CoA reductase.' Beyond the LDL lowering activity of statins, improvements have been noted in endothelial dysfunction through direct stimulation of expression of such vasodilators as nitric oxide and/or reduction in vasoconstrictors. Factors associated with atherogenesis, such as monocyte adhesion to endothelial cells, macrophage production of proinflammatory molecules and matrix metalloproteases, smooth muscle cell proliferation and migration and macrophage-induced oxidation of LDL particles have also been reduced by various statins. It is unclear whether the observed pleiotropic effects are independent of LDL-cholesterol lowering or inhibition of HMG-CoA reductase, and whether they are clinically relevant; however, one can conclude that the pleiotropic effects appear to be a class effect of statins and can be attenuated by addition of the post-reductase product, mevalonate.
Background:
Throughout the usual LDL cholesterol range in Western populations, lower blood concentrations are associated with lower cardiovascular disease risk. In such populations, therefore, reducing LDL cholesterol may reduce the development of vascular disease, largely irrespective of initial cholesterol concentrations.
Methods:
20,536 UK adults (aged 40-80 years) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive 40 mg simvastatin daily (average compliance: 85%) or matching placebo (average non-study statin use: 17%). Analyses are of the first occurrence of particular events, and compare all simvastatin-allocated versus all placebo-allocated participants. These "intention-to-treat" comparisons assess the effects of about two-thirds (85% minus 17%) taking a statin during the scheduled 5-year treatment period, which yielded an average difference in LDL cholesterol of 1.0 mmol/L (about two-thirds of the effect of actual use of 40 mg simvastatin daily). Primary outcomes were mortality (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity.
Findings:
All-cause mortality was significantly reduced (1328 [12.9%] deaths among 10,269 allocated simvastatin versus 1507 [14.7%] among 10,267 allocated placebo; p=0.0003), due to a highly significant 18% (SE 5) proportional reduction in the coronary death rate (587 [5.7%] vs 707 [6.9%]; p=0.0005), a marginally significant reduction in other vascular deaths (194 [1.9%] vs 230 [2.2%]; p=0.07), and a non-significant reduction in non-vascular deaths (547 [5.3%] vs 570 [5.6%]; p=0.4). There were highly significant reductions of about one-quarter in the first event rate for non-fatal myocardial infarction or coronary death (898 [8.7%] vs 1212 [11.8%]; p<0.0001), for non-fatal or fatal stroke (444 [4.3%] vs 585 [5.7%]; p<0.0001), and for coronary or non-coronary revascularisation (939 [9.1%] vs 1205 [11.7%]; p<0.0001). For the first occurrence of any of these major vascular events, there was a definite 24% (SE 3; 95% CI 19-28) reduction in the event rate (2033 [19.8%] vs 2585 [25.2%] affected individuals; p<0.0001). During the first year the reduction in major vascular events was not significant, but subsequently it was highly significant during each separate year. The proportional reduction in the event rate was similar (and significant) in each subcategory of participant studied, including: those without diagnosed coronary disease who had cerebrovascular disease, or had peripheral artery disease, or had diabetes; men and, separately, women; those aged either under or over 70 years at entry; and--most notably--even those who presented with LDL cholesterol below 3.0 mmol/L (116 mg/dL), or total cholesterol below 5.0 mmol/L (193 mg/dL). The benefits of simvastatin were additional to those of other cardioprotective treatments. The annual excess risk of myopathy with this regimen was about 0.01%. There were no significant adverse effects on cancer incidence or on hospitalisation for any other non-vascular cause.
Interpretation:
Adding simvastatin to existing treatments safely produces substantial additional benefits for a wide range of high-risk patients, irrespective of their initial cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rates of myocardial infarction, of stroke, and of revascularisation by about one-quarter. After making allowance for non-compliance, actual use of this regimen would probably reduce these rates by about one-third. Hence, among the many types of high-risk individual studied, 5 years of simvastatin would prevent about 70-100 people per 1000 from suffering at least one of these major vascular events (and longer treatment should produce further benefit). The size of the 5-year benefit depends chiefly on such individuals' overall risk of major vascular events, rather than on their blood lipid concentrations alone.
Background— The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial showed that pravastatin significantly reduced mortality and coronary heart disease (CHD) events in 9014 patients with known CHD and total cholesterol 4.0 to 7.0 mmol/L at baseline. Secondary objectives included assessment of CHD event reduction according to lipid levels.
Methods and Results— We investigated the relationships of baseline and on-study lipids with subsequent CHD events in separate Cox models. Treatment effect on CHD event reduction was examined by baseline lipids and after adjustment for on-study lipid levels. Baseline lipids were significant predictors of CHD events. The adjusted relative risk per mmol/L (on placebo) was 1.24 (P=0.004) for total cholesterol, 1.28 (P=0.002) for low-density lipoprotein cholesterol, and 0.52 (P=0.004) for high-density lipoprotein cholesterol. Apolipoproteins A1 and B were strong predictors (each P=0.001). Pravastatin reduced the risk of the composite outcome of fatal CHD or nonfatal myocardial infarction by 24% (95% confidence interval [CI], 15% to 32%) and the expanded end point of fatal CHD, nonfatal myocardial infarction, unstable angina, or coronary revascularization by 17% (95% CI, 10% to 24%). Similar relative effects were observed for different categories of baseline lipids. The proportion of treatment effect explained by on-study lipid levels was 67% (95% CI, 27% to 106%) for the composite and 97% (95% CI, 49% to 145%) for the expanded end point. The most important lipids associated with event reduction were apolipoprotein B, low-density lipoprotein cholesterol, and the combination of total and high-density lipoprotein cholesterol.
Conclusions— Changes in lipid levels can explain all or most of the observed benefit of pravastatin. Some treatment effect may also be mediated through nonlipid changes.
Drug therapy for hypercholesterolaemia has remained controversial mainly because of insufficient clinical trial evidence for improved survival. The present trial was designed to evaluate the effect of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease (CHD). 4444 patients with angina pectoris or previous myocardial infarction and serum cholesterol 5·5-8·0 mmol/L on a lipid-lowering diet were randomised to double-blind treatment with simvastatin or placebo.Over the 5·4 years median follow-up period, simvastatin produced mean changes in total cholesterol, low-density-lipoprotein cholesterol, and high-density-lipoprotein cholesterol of -25%, -35%, and +8%, respectively, with few adverse effects. 256 patients (12%) in the placebo group died, compared with 182 (8%) in the simvastatin group. The relative risk of death in the simvastatin group was 0·70 (95% Cl 0·58-0·85, p=0·0003). The 6-year· probabilities of survival in the placebo and simvastatin groups were 87·6% and 91·3%, respectively. There were 189 coronary deaths in the placebo group and 111 in the simvastatin group (relative risk 0·58, 95% Cl 0·46-0·73), while noncardiovascular causes accounted for 49 and 46 deaths, respectively. 622 patients (28%) in the placebo group and 431 (19%) in the simvastatin group had one or more major coronary events. The relative risk was 0·66 (95% Cl 0·59-0·75, p<0·00001), and the respective probabilities of escaping such events were 70·5% and 79·6%. This risk was also significantly reduced in subgroups consisting of women and patients of both sexes aged 60 or more. Other benefits of treatment included a 37% reduction (p<0·00001) in the risk of undergoing myocardial revascularisation procedures.This study shows that long-term treatment with simvastatin is safe and improves survival in CHD patients.
Genes have a major role in the control of high-density lipoprotein (HDL) cholesterol (HDL-C) levels. Here we have identified two Tangier disease (TD) families, confirmed 9q31 linkage and refined the disease locus to a limited genomic region containing the gene encoding the ATP-binding cassette transporter (ABC1). Familial HDL deficiency (FHA) is a more frequent cause of low HDL levels. On the basis of independent linkage and meiotic recom-binants, we localized the FHA locus to the same genomic region as the TD locus. Mutations in ABC1 were detected in both TD and FHA, indicating that TD and FHA are allelic. This indicates that the protein encoded by ABC1 is a key gatekeeper influencing intracellular cholesterol transport, hence we have named it cholesterol efflux regulatory protein (CERP).
Rheumatoid arthritis (RA) is a prototypical immune-mediated inflammatory disease that is characterized by increased cardiovascular morbidity and mortality, independent of the traditional risk factors for cardiovascular disease. The chronic inflammatory state--a hallmark of RA--is considered to be a driving force for accelerated atherogenesis. Consequently, aggressive control of RA disease activity is thought to be instrumental for cardiovascular risk reduction. Currently, statin-mediated reduction of LDL-cholesterol levels is considered to be the cornerstone of cardiovascular disease prevention. In addition to their lipid-lowering capabilities, statins exert immunomodulatory effects, which could be of dual benefit in the treatment of RA. Guidelines on the reduction of cardiovascular risk in patients with RA are lacking, however, largely owing to the absence of data from randomized controlled trials. This Review focuses on the pathophysiology of cardiovascular events in RA, as well as the need to adjust cardiovascular risk engines to better-accommodate the impact of chronic inflammatory disease over and above the established risk factors to predict cardiovascular risk in patients with RA.
Human plasma apolipoprotein A-I (apoA-I) has been studied in an aqueous solution by the techniques of high performance liquid chromatography (HPLC), circular dichroic spectroscopy, and sedimentation equilibrium ultracentrifugation. The results indicate that an oligomer is formed as an intermediate step of dissolving lyophilized apoA-I. The process of further dissolution of this oligomer is an irreversible, temperature-dependent dissociation. The half-life of this intermediate oligomer is 3 min at 37°C and 80 h at 30°C. The completely dissolved apoA-I in an aqueous buffer self-associates with conformational alteration. The self-association equilibrium is too rapid to be demonstrated by HPLC.
In this article, the history of the LDL receptor is recounted by its codiscoverers. Their early work on the LDL receptor explained a genetic cause of heart attacks and led to new ways of thinking about cholesterol metabolism. The LDL receptor discovery also introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. The latter concept provides the mechanism by which statins selectively lower plasma LDL, reducing heart attacks and prolonging life.
We studied 56 patients affected by primary hypercholesterolemia treated with placebo for 1 month and with simvastatin (20 mg/day) or pravastatin (20 mg/day) for 6 months during a double-blind clinical trial. At 1-month intervals we determined the following parameters in the serum: total and HDL cholesterol, triglycerides, and apolipoprotein A-1 and B. At the