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ABSTRACT: LDs (lipid droplets) are metabolically highly active intracellular organelles. The lipid and protein profiles of LDs are cell-type-specific, and they undergo dynamic variation upon changes in the physiological state of a cell. It is well known that the main function of the LDs in adipocytes is to ensure energy supply and to maintain lipid homoeostasis in the body. In contrast, LDs in inflammatory cells have been implicated in eicosanoid biosynthesis, particularly under inflammatory conditions, thereby enabling them to regulate immune responses. Human mast cells are potent effector cells of the innate immune system, and the triacylglycerol (triglyceride) stores of their cytoplasmic LDs have been shown to contain large amounts of arachidonic acid, the main precursor of pro-inflammatory eicosanoids. In the present review, we discuss the current knowledge about the formation and function of LDs in inflammatory cells with specific emphasis on arachidonic acid and eicosanoid metabolism. On the basis of findings reported previously and our new observations, we propose a model in which lipolysis of LD-triacylglycerols provides arachidonic acid for lipid mediator generation in human mast cells.
Clinical Science 08/2013; 125(3):121-30. · 4.61 Impact Factor
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ABSTRACT: In the arterial intima, macrophages become cholesterol-enriched foam cells and atherosclerotic lesions are generated. This atherogenic process can be attenuated, prevented, or even reversed by HDL particles capable of initiating a multistep pathway known as the macrophage-specific reverse cholesterol transport. The macrophage-derived cholesterol released to HDL is taken up by the liver, secreted into the bile, and ultimately excreted in the feces. Importantly, the absorptive epithelial cells lining the lumen of the small intestine, the enterocytes, express several membrane-associated proteins which mediate the influx of luminal cholesterol and its subsequent efflux at their apical and basolateral sides. Moreover, generation of intestinal HDL and systemic effects of the gut microbiota recently revealed a direct link between the gut and the cholesterol cargo of peripheral macrophages. This review summarizes experimental evidence establishing that the reverse cholesterol transport pathway which initiates in macrophages is susceptible to modulation in the small intestine. We also describe 4 paths which govern cholesterol passage across the enterocyte and define a role for the gut in the regulation of reverse cholesterol transport. Understanding the concerted function of these paths may be useful when designing therapeutic strategies aimed at removing cholesterol from the foam cells which occupy atherosclerotic lesions.
Progress in lipid research 04/2013; · 10.67 Impact Factor
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ABSTRACT: BACKGROUND: Human tissue mast cells (MCs) have the potential to express several neutral granule proteases, which are the most precise markers of the phenotypic heterogeneity of MCs. However, the full extent of such heterogeneity is limited by the fact that MCs containing either tryptase only or tryptase and chymase have long been considered to be the sole MC phenotypes. Moreover, the potential developmental relationship between human MCs of different protease phenotypes has remained a matter of dispute. OBJECTIVE: We attempted to define how human MCs with different protease phenotypes relate to their circulating progenitors. METHODS: MCs were generated from human peripheral blood-derived CD34(+) progenitors in the presence of kit ligand (KITLG) and the cytokines IL-3, IL-9, and IL-6 under serum-free conditions, or by KITLG alone in the presence or absence of serum. The expression of chymase, carboxypeptidase A3, cathepsin G, granzyme B, and the tryptases derived from the TPSAB1, TPSB2, TPSD1, and TPSG1/PRSS31 genes were determined weekly at the mRNA and/or protein levels. RESULTS: Incubation of CD34(+) progenitors in the presence of KITLG and the cytokines IL-3, IL-9, and IL-6 promoted the development of a single population of MCs with a uniform tryptase(+), chymase(+), CPA3(+), cathepsin G(+), and granzyme B(+) phenotype. Interestingly, the presence of KITLG alone was sufficient to induce the expression of all the above proteases. CONCLUSION: All circulating human MC progenitors have the potential to differentiate into MCs expressing the complete panel of neutral granule proteases, implying that human MCs originate from a common MC-committed progenitor.
The Journal of allergy and clinical immunology 04/2013; · 9.17 Impact Factor
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ABSTRACT: OBJECTIVE: Premenopausal women have a lower incidence of cardiovascular disease compared to men of the same age. Endogenous oestrogens, especially estradiol, presumably protect against atherosclerosis by a variety of mechanisms. Reverse cholesterol transport (RCT) mechanisms also provide protection against this disease. RCT is defined as the removal of cholesterol from peripheral macrophage foam cells, via high-density lipoproteins (HDL), and cholesterol transportation to the liver for excretion. We have previously shown in a preliminary study that HDL, isolated from premenopausal women, enhanced macrophage cholesterol efflux compared to HDL derived from age-matched male subjects. MATERIALS AND METHODS: Here, we expanded this study by analysing a larger population of healthy volunteers and evaluated the capacity of HDL derived from women with high or low serum E2 concentrations, mainly representing premenopausal and postmenopausal women, respectively, or men (each group consisting of 30 subjects) to facilitate cholesterol removal from human THP-1 macrophages. HDL isolated from serum samples was incubated with [(3) H] cholesterol oleate-loaded macrophages for 16 h, after which cholesterol efflux to HDL was determined. RESULTS: No significant differences in the efflux-promoting ability of HDL existed among the three groups. Relevant plasma factors involved in further steps of RCT, such as cholesterol ester transfer protein (CETP), phospholipid transfer protein (PLTP) and lecithin:cholesterol acyltransferase (LCAT) activities were also analysed, but no differences were observed among the study groups. CONCLUSION: The results do not support a role for estradiol status or gender in modifying the initial step of RCT as a protective mechanism against cardiovascular disease.
European Journal of Clinical Investigation 12/2012; · 3.02 Impact Factor
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ABSTRACT: A high-fat diet disturbs the composition and function of the gut microbiota and generates local gut-associated and also systemic responses. Intestinal mast cells, for their part, secrete mediators which play a role in the orchestration of physiological and immunological functions of the intestine. Probiotic bacteria, again, help to maintain the homeostasis of the gut microbiota by protecting the gut epithelium and regulating the local immune system. In the present study, we explored the effects of two probiotic bacteria, Lactobacillus rhamnosus GG (GG) and Propionibacterium freudenreichii spp. shermanii JS (PJS), on high fat-fed ApoE*3Leiden mice by estimating the mast cell numbers and the immunoreactivity of TNF-α and IL-10 in the intestine, as well as plasma levels of several markers of inflammation and parameters of lipid metabolism. We found that mice that received GG and PJS exhibited significantly lower numbers of intestinal mast cells compared with control mice. PJS lowered intestinal immunoreactivity of TNF-α, while GG increased intestinal IL-10. PJS was also observed to lower the plasma levels of markers of inflammation including vascular cell adhesion molecule 1, and also the amount of gonadal adipose tissue. GG lowered alanine aminotransferase, a marker of hepatocellular activation. Collectively, these data demonstrate that probiotic GG and PJS tend to down-regulate both intestinal and systemic pro-inflammatory changes induced by a high-fat diet in this humanised mouse model.
The British journal of nutrition 12/2012; · 3.45 Impact Factor
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ABSTRACT: OBJECTIVE: Periodontitis, a chronic oral infection caused mainly by gram-negative bacteria, induces endotoxemia and associates with the risk for atherosclerosis. We investigated the effect of periodontal treatment on proatherogenic properties of very low density lipoproteins (VLDL). METHODS: VLDL were isolated from 30 systemically healthy periodontitis patients before (pre-treatment) and 3months after treatment (post-treatment). The mass compositions were analyzed, and VLDL-induced changes in cellular cholesterol content and expression of selected genes of human THP-1 macrophages were measured. RESULTS: Periodontal treatment decreased the local inflammation in the periodontium, but did not have a significant effect on C-reactive protein (CRP) levels, VLDL composition, or VLDL potential to induce cholesterol uptake or gene expression by the macrophages. Incubation of macrophages in the presence of VLDL resulted in more than twofold increase in their cellular cholesterol content. Uptake of VLDL with ensuing macrophage cholesterol accumulation correlated positively with VLDL-associated lipopolysaccharide (LPS) activity (r=0.436, P=.016) and apolipoprotein E content (r=0.374, P=.046). Pre-treatment VLDL derived from the patients with high CRP levels displayed higher LPS activity than that of VLDL derived from patients with low CRP (above vs. below median, P=.007). In addition, pre-treatment VLDL isolated from patients with high systemic inflammation induced higher relative mRNA expression of CD14, TNF-α, MCP-1, and IL-6 in the macrophages. CONCLUSION: Inflammation and endotoxemia induced by severe periodontitis may increase VLDL-dependent macrophage activation and cellular cholesterol accumulation, and thereby atherogenesis.
Metabolism: clinical and experimental 12/2012; · 2.59 Impact Factor
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Olli T Raitakari,
Ville-Petteri Mäkinen,
Matthew J McQueen,
Jaakko Niemi,
Markus Juonala,
Matti Jauhiainen,
Veikko Salomaa,
Minna L Hannuksela,
Markku J Savolainen,
Y Antero Kesäniemi, [......],
Terho Lehtimäki,
Mika Kähönen,
Markku Peltonen,
Jaana Leiviskä,
Antti Jula,
Sonia S Anand,
Ruby Miller,
Salim Yusuf,
Jorma S A Viikari,
Mika Ala-Korpela
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ABSTRACT: OBJECTIVE: Apolipoproteins B (apoB) and A1 (apoA1) may be better markers of atherosclerosis than serum lipids. We used computational methods to estimate apoB and apoA1 from serum total cholesterol, HDL-cholesterol and triglycerides and tested their clinical value in comparison to measured apoB and apoA1 values. METHODS: ApoB and apoA1 were measured with standard methods and estimated based on neural network regression models in 2166 young adult with data on carotid artery intima-media thickness (cIMT). RESULTS: Correlations between estimated and measured apoB and apoA1 were r = 0.98 and r = 0.95, respectively. ApoB/apoA1-ratio (both measured and estimated) associated with cIMT in multivariable models, and predicted cIMT at all levels of LDL-cholesterol concentration. Strong correlations between the estimated apolipoproteins and those measured from fasting samples were replicated in over 15,000 Caucasian subjects (r = 0.93-0.96 for apoB and r = 0.91-0.92 for apoA1). Correlations with cIMT were replicated in over 2000 individuals. Estimated apoB/apoA1-ratio calculated from non-fasting lipids in over 20,000 individuals in the INTERHEART study was better than any of the cholesterol measures for estimation of the myocardial risk. CONCLUSIONS: Serum cholesterol, HDL-cholesterol and triglycerides can be used to compute clinically useful estimates of apoB and apoA1. Using this methodology, estimates of apolipoproteins could be routinely added to laboratory reports to complement lipoprotein lipids in risk assessment.
Atherosclerosis 11/2012; · 3.79 Impact Factor
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ABSTRACT: In the heterozygous form of familial hypercholesterolemia (FH), blood concentrations of low-density lipoprotein cholesterol (LDL-C) are elevated two to three times above the normal range since birth, and cause strongly elevated risk of premature coronary artery disease (CAD). There is no evidence that statin therapy is unsafe in FH children, and it has not been associated with clinically significant changes in measures of growth or maturation, liver enzymes, serum creatine kinase, or incidence of myopathy. However, the opinions among clinicians, and between countries, about the age at which statin therapy should be initiated in FH children vary. This review attempts to critically examine the available data, so that clinically the most appropriate age of initiating statin treatment in FH children as a preventive measure for future CAD could be established.
Atherosclerosis 10/2012; · 3.79 Impact Factor
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Reija Silvennoinen,
Joan Carles Escola-Gil,
Josep Julve,
Noemi Rotllan,
Gemma Llaverias,
Jari Metso,
Annabel F Valledor,
Jianming He,
Liqing Yu,
Matti Jauhiainen,
Francisco Blanco-Vaca, Petri T Kovanen,
Miriam Lee-Rueckert
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ABSTRACT: Rationale: Psychological stress is associated with an increased risk of cardiovascular diseases. However, the connecting mechanisms of the stress-inducing activation of the hypothalamic-pituitary-adrenal axis with atherosclerosis are not well understood. Objective: To study the effect of acute psychological stress on reverse cholesterol transport (RCT), which transfers peripheral cholesterol to the liver for its ultimate fecal excretion. Methods and Results: C57Bl/6J mice were exposed to restraint stress for 3 h to induce acute psychological stress. RCT in vivo was quantified by measuring the transfer of [(3)H]cholesterol from intraperitoneally injected mouse macrophages to the lumen of the small intestine within the stress period. Surprisingly, stress markedly increased the contents of macrophage-derived [(3)H]cholesterol in the intestinal lumen. In the stressed mice, intestinal absorption of [(14)C]cholesterol was significantly impaired, the intestinal mRNA expression level of peroxisome proliferator-activated receptor α (PPARα) increased, and that of the sterol influx transporter Niemann-Pick C1-like 1 (NPC1L1) decreased. The stress-dependent effects on RCT rate and PPARα gene expression were fully mimicked by administration of the stress hormone corticosterone to non-stressed mice, and they were blocked by the inhibition of corticosterone synthesis in stressed mice. Moreover, the intestinal expression of NPC1L1 protein decreased when circulating levels of corticosterone increased. Of note, when either PPARα- or LXRα-knockout mice were exposed to stress, the RCT rate remained unchanged, although plasma corticosterone increased. This indicates that activities of both transcription factors were required for the RCT-accelerating effect of stress. Conclusions: Acute psychological stress accelerated RCT by compromising intestinal cholesterol absorption. The present results uncover a novel functional connection between the hypothalamic-pituitary-adrenal axis and RCT that can be triggered by a stress-induced increase in circulating corticosterone.
Circulation Research 08/2012; · 9.49 Impact Factor
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ABSTRACT: HDL particles may enter atherosclerotic lesions having an acidic intimal fluid. Therefore, we investigated whether acidic pH would affect their structural and functional properties. For this purpose, HDL(2) and HDL(3) subfractions were incubated for various periods of time at different pH values ranging from 5.5 to 7.5, after which their protein and lipid compositions, size, structure, and cholesterol efflux capacity were analyzed. Incubation of either subfraction at acidic pH induced unfolding of apolipoproteins, which was followed by release of lipid-poor apoA-I and ensuing fusion of the HDL particles. The acidic pH-modified HDL particles exhibited an enhanced ability to promote cholesterol efflux from cholesterol-laden primary human macrophages. Importantly, treatment of the acidic pH-modified HDL with the mast cell-derived protease chymase completely depleted the newly generated lipid-poor apoA-I, and prevented the acidic pH-dependent increase in cholesterol efflux. The above-found pH-dependent structural and functional changes were stronger in HDL(3) than in HDL(2). Spontaneous acidic pH-induced remodeling of mature spherical HDL particles increases HDL-induced cholesterol efflux from macrophage foam cells, and therefore may have atheroprotective effects.
The Journal of Lipid Research 08/2012; 53(10):2115-25. · 5.56 Impact Factor
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ABSTRACT: During atherogenesis, the extracellular pH of atherosclerotic lesions decreases. Here, we examined the effect of low, but physiologically plausible pH on aggregation of modified LDL, one of the key processes in atherogenesis. LDL was treated with SMase, and aggregation of the SMase-treated LDL was followed at pH 5.5-7.5. The lower the pH, the more extensive was the aggregation of identically prelipolyzed LDL particles. At pH 5.5-6.0, the aggregates were much larger (size >1 µm) than those formed at neutral pH (100-200 nm). SMase treatment was found to lead to a dramatic decrease in α-helix and concomitant increase in β-sheet structures of apoB-100. Particle aggregation was caused by interactions between newly exposed segments of apoB-100. LDL-derived lipid microemulsions lacking apoB-100 failed to form large aggregates. SMase-induced LDL aggregation could be blocked by lowering the incubation temperature to 15°C, which also inhibited the changes in the conformation of apoB-100, by proteolytic degradation of apoB-100 after SMase-treatment, and by HDL particles. Taken together, sphingomyelin hydrolysis induces exposure of protease-sensitive sites of apoB-100, whose interactions govern subsequent particle aggregation. The supersized LDL aggregates may contribute to the retention of LDL lipids in acidic areas of atherosclerosis-susceptible sites in the arterial intima.
The Journal of Lipid Research 06/2012; 53(9):1832-9. · 5.56 Impact Factor
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ABSTRACT: Atherosclerosis is initiated when lipoproteins bind to proteoglycans (PGs) in arterial walls. The binding is mediated by apolipoprotein apoB-100 and/or apoE, both of which have binding affinity toward heparin. We developed covalently bound heparin coatings for APTES-modified silica capillaries and SiO(2) chips and carried out capillary electrochromatography (CEC) and quartz crystal microbalance (QCM) studies on the interactions of heparin with selected peptide fragments of apoB-100 and apoE and, for CEC, also with low- and high-density lipoproteins (LDL and HDL), the latter with and without apoE. The peptides are known to mediate interactions of HDL and LDL with arterial PGs. Interactions and affinities were expressed in CEC as retention factors and reduced mobilities and in continuous flow QCM techniques as affinity constants. Both techniques showed heparin interactions to be stronger with apoB-100 peptide than with apoE peptide fragment, and they confirmed that the sulfate groups in heparin play an especially important role in interactions with apoB-100 peptide fragments. In addition, CEC confirmed the importance of sulfate groups of heparin in interactions between heparin and LDL and between heparin and apoE-containing HDL. CEC and QCM acted as excellent platforms to mimic these biologically important interactions, with small sample and reagent consumption.
Analytical Biochemistry 02/2012; 424(1):71-8. · 3.00 Impact Factor
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ABSTRACT: Local acidic areas characterize diffuse intimal thickening (DIT) and advanced atherosclerotic lesions. The role of acidity in the modification and extra- and intracellular accumulation of triglyceride-rich VLDL and IDL particles has not been studied before. Here, we examined the effects of acidic pH on the activity of recombinant human group V secreted phospholipase A(2) (sPLA(2)-V) toward small VLDL (sVLDL), IDL, and LDL, on the binding of these apoB-100-containing lipoproteins to human aortic proteoglycans, and on their uptake by human monocyte-derived macrophages. At acidic pH, the ability of sPLA(2)-V to lipolyze the apoB-100-containing lipoproteins was moderately, but significantly, increased while binding of the lipoproteins to proteoglycans increased >60-fold and sPLA(2)-V-modification further doubled the binding. Moreover, acidic pH more than doubled macrophage uptake of soluble complexes of sPLA(2)-V-LDL with aortic proteoglycans. Proteoglycan-affinity chromatography at pH 7.5 and 5.5 revealed that sVLDL, IDL, and LDL consisted of populations with different proteoglycan-binding affinities, and, surprisingly, the sVLDL fractions with the highest proteoglycan-affinity contained only low amounts of apolipoproteins E and C-III. Our results suggest that in atherosclerotic lesions with acidic extracellular pH, sPLA(2)-V is able to lipolyze sVLDL, IDL, and LDL, and increase their binding to proteoglycans. This is likely to provoke extracellular accumulation of lipids derived from these atherogenic lipoprotein particles and to increase the progression of the atherosclerotic lesions.
Biochimica et Biophysica Acta 02/2012; 1821(2):257-67. · 4.66 Impact Factor
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ABSTRACT: Accumulating work in experimental animals suggests that bradykinin (BK) exerts cardioprotective effects via bradykinin type-2 receptors (BK-2Rs). In human end-stage heart failure, BK-2Rs are significantly downregulated by mechanisms that have remained elusive. Heart tissues from idiopathic dilated cardiomyopathy (IDC; n = 7), coronary heart disease (CHD; n = 6), and normal patients (n = 6) were analyzed by RT-PCR, SSCP, and Western blotting. In normal and IDC hearts, BK-2R expression increased with age, with a lower relative increase in IDC hearts. BK-2R mRNA and protein levels showed a positive linear correlation, suggesting transcriptional regulation. Two known BK-2R promoter polymorphisms, -58T/C and -9/+9, were found to be present in the study population. The allelic frequencies for the C-allele in -58T/C were 0.58 in normal and CHD hearts and 0.81 in IDC hearts. Furthermore, the allelic frequencies for the -9 and +9 alleles were 0.42 and 0.58 in normal hearts and 0.64 and 0.36 in IDC hearts, respectively. All analyzed CHD hearts were homozygous for the -9 allele. Thus, the expression of cardioprotective BK-2Rs in human hearts is increased with age in normal and IDC hearts and may be regulated on the transcriptional level. Moreover, comparison of normal subjects and patients with failing hearts revealed different allelic frequencies in each of two known BK-2R gene polymorphisms.
International journal of vascular medicine 01/2012; 2012:159646.
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ABSTRACT: Bradykinin type 2 receptor (BK-2R) knockout mice develop microvascular dysfunction and cardiac hypertrophy. In aged human cardiac microvascular endothelium, dysfunction develops before heart failure symptoms. Since endothelial aging is an independent risk factor for cardiovascular disease, we aimed to clarify the role of kinin receptors in age-related endothelial senescence.
Using qRT-PCR, a downregulation of BK-2Rs during senescence of cultured human coronary artery endothelial cells (HCAECs) and rat cardiac microvascular endothelial cells (RCMECs) was observed. BK-2R downregulation was associated with a decreased cell proliferation rate, with a growth arrest phenotype and reduced angiogenic potential. By staining senescence-associated β-galactosidase, RCMECs from old spontaneously hypertensive rats (SHRs) were found to be significantly more senescent than those derived from age-matched WKY rats, albeit their telomere lengths were similar. Despite downregulation of BK-2Rs and BK-1Rs, a novel family member GPR-100 was highly expressed in HCAECs throughout the culture period.
Aging cardiac endothelial cells gradually lose their capacity to express BK-2Rs, and this loss appears to be parallel with a loss of the angiogenic potential of the aging cells. Since RCMECs from hypertensive rats showed premature senescence, hypertension may predispose to cardiac dysfunction by accelerating endothelial aging.
Journal of Vascular Research 01/2012; 49(1):13-23. · 2.65 Impact Factor
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ABSTRACT: Cholesteryl ester transfer protein (CETP) transports cholesteryl esters, triglycerides, and phospholipids between different lipoprotein fractions in blood plasma. The inhibition of CETP has been shown to be a sound strategy to prevent and treat the development of coronary heart disease. We employed molecular dynamics simulations to unravel the mechanisms associated with the CETP-mediated lipid exchange. To this end we used both atomistic and coarse-grained models whose results were consistent with each other. We found CETP to bind to the surface of high density lipoprotein (HDL) -like lipid droplets through its charged and tryptophan residues. Upon binding, CETP rapidly (in about 10 ns) induced the formation of a small hydrophobic patch to the phospholipid surface of the droplet, opening a route from the core of the lipid droplet to the binding pocket of CETP. This was followed by a conformational change of helix X of CETP to an open state, in which we found the accessibility of cholesteryl esters to the C-terminal tunnel opening of CETP to increase. Furthermore, in the absence of helix X, cholesteryl esters rapidly diffused into CETP through the C-terminal opening. The results provide compelling evidence that helix X acts as a lid which conducts lipid exchange by alternating the open and closed states. The findings have potential for the design of novel molecular agents to inhibit the activity of CETP.
PLoS Computational Biology 01/2012; 8(1):e1002299. · 5.22 Impact Factor
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ABSTRACT: To investigate mechanisms of lymphangiogenesis in aortic valve stenosis (AS).
Lymphatic vessels were visualized with LYVE-1 staining in 20 control, 5 sclerotic, and 40 stenotic human aortic valves. Vascular endothelial growth factors (VEGFs) VEGF-C and VEGF-D, and their lymphangiogenic receptor VEGFR-3, and the angiogenic VEGFR-2 were analysed by quantitative real-time PCR and immunohistochemistry. Cultured myofibroblasts derived from human stenotic aortic valves, and cultured human mast cells were used to study VEGF-C regulation, and VEGF-C and VEGF-A were quantified from cell culture media by enzyme immunoassays.
Lymphatic vessels, VEGF-C, VEGF-D, VEGFR-3 and VEGFR-2 all were present in the aortic valves. In AS, the number of lymphatic vessels and the expression of VEGF-D, VEGFR-3, and VEGFR-2 were increased. Moreover, the numbers of lymphatic vessels correlated positively with those of neovessels (r = 0.525, p = 0.001) and mast cells (r = 0.374, p = 0.017). Cultured valvular myofibroblasts produced VEGF-C, and addition of tumour necrosis factor alpha (TNF-α) to the cells augmented its secretion. In contrast, proteases released by activated human mast cells degraded VEGF-C.
These results show that lymphangiogenesis is induced in advancing AS. Furthermore, valvular myofibroblasts and activated mast cells were identified as novel regulators of lymphangiogenesis in aortic valves.
Atherosclerosis 12/2011; 221(2):366-74. · 3.79 Impact Factor
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ABSTRACT: Lipid droplets, also called lipid bodies (LB) in inflammatory cells, are important cytoplasmic organelles. However, little is known about the molecular characteristics and functions of LBs in human mast cells (MC). Here, we have analyzed the genesis and components of LBs during differentiation of human peripheral blood-derived CD34(+) progenitors into connective tissue-type MCs. In our serum-free culture system, the maturing MCs, derived from 18 different donors, invariably developed triacylglycerol (TG)-rich LBs. Not known heretofore, the MCs transcribe the genes for perilipins (PLIN)1-4, but not PLIN5, and PLIN2 and PLIN3 display different degrees of LB association. Upon MC activation and ensuing degranulation, the LBs were not cosecreted with the cytoplasmic secretory granules. Exogenous arachidonic acid (AA) enhanced LB genesis in Triacsin C-sensitive fashion, and it was found to be preferentially incorporated into the TGs of LBs. The large TG-associated pool of AA in LBs likely is a major precursor for eicosanoid production by MCs. In summary, we demonstrate that cultured human MCs derived from CD34(+) progenitors in peripheral blood provide a new tool to study regulatory mechanisms involving LB functions, with particular emphasis on AA metabolism, eicosanoid biosynthesis, and subsequent release of proinflammatory lipid mediators from these cells.
The Journal of Lipid Research 12/2011; 52(12):2198-208. · 5.56 Impact Factor
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ABSTRACT: Both quantity and quality of the circulating HDL particle matter for the optimal antiatherogenic potential of HDL. This review summarizes various mechanisms capable of inducing extracellular modifications of HDL and reducing the function of HDL subclasses as cholesterol acceptors. Special emphasis is laid on the proteolytic inactivation of lipid-poor preβ-migrating HDL (preβ-HDL).
HDL particles can undergo functional inactivation in vivo. During atherogenesis, different cell types in the arterial intima release enzymes into the intimal fluid, potentially capable of causing structural and chemical modifications of the various components present in the lipid core or in the polar surface of the HDL particles. Enzymatic oxidation, lipolysis and proteolysis, and nonenzymatic glycosylation are among the HDL modifications that adversely affect HDL functionality. Proteolysis of preβ-HDL by various proteases present in the arterial intima has emerged as a potential mechanism that impairs the efficiency of HDL to promote cholesterol efflux from macrophage foam cells, the mast cell-derived neutral protease chymase being a prime example of such impairment. A paradigm of proteolytic inactivation of preβ-HDL in vivo is emerging.
Several extracellular enzymes present in the arterial intima may compromise various cardioprotective functions of HDL. Observations on proteolysis of specific lipid-poor HDL subpopulations in vivo constitute the basis for future studies evaluating the actual impact of proteolytic microenvironments on the initiation and progression of atherosclerotic lesions.
Current opinion in lipidology 08/2011; 22(5):394-402. · 6.13 Impact Factor
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ABSTRACT: To determine whether differences exist in valvular high density lipoprotein (HDL) content between non-stenotic and stenotic aortic valves, and whether HDL could retard valvular calcification locally.
Stenotic aortic valves were obtained from valve replacement surgery and non-stenotic control valves from cardiac transplantations or at autopsy. The valvular localization and concentration of apolipoproteinA-I (apoA-I) were analyzed by immunohistochemistry and ELISA. The effects of HDL on the secretion of calcifying mediators and proinflammatory cytokines by cultured aortic valve myofibroblasts were assessed by ELISA and real-time PCR.
The concentration of apoA-I was higher in control than in stenotic valves (p < 0.05). ApoA-I surrounded the calcific deposits in stenotic valves, co-localizing with apoB, apoE, and osteoprotegerin (OPG). Incubation of cultured valve myofibroblasts with HDL increased their secretion of OPG (p < 0.001). Furthermore, incubation of myofibroblasts with HDL led to decreased mRNA expression of tumor necrosis factor alpha (TNF-α) (p < 0.05).
The amount of valvular HDL is reduced in aortic valve stenosis. HDL both induces the secretion of OPG and reduces the expression of TNF-α in vitro. Since OPG is known to inhibit and TNF-α to promote aortic valve calcification, HDL may have an anti-calcifying effect in human aortic valves.
Atherosclerosis 08/2011; 219(2):538-44. · 3.79 Impact Factor
