Publications (76)381.17 Total impact
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Article: Suppressors of cytokine signaling modulate JAK/STAT-mediated cell responses during atherosclerosis.
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ABSTRACT: Suppressors of cytokine signaling (SOCS) proteins are intracellular regulators of receptor signal transduction, mainly Janus kinase/signal transducers and activators of transcription (JAK/STAT). We investigated the effects of SOCS modulation on the JAK/STAT-dependent responses in vascular cells, and their implication in atherosclerotic plaque development. Immunohistochemistry in human plaques revealed a high expression of SOCS1 and SOCS3 by vascular smooth muscle cells (VSMCs) and macrophages in the inflammatory region of the shoulders, when compared to the fibrous area. SOCS were also increased in aortic lesions from apoE(-/-) mice. In cultured VSMCs, endothelial cells, and monocytes, SOCS1 and SOCS3 were transiently induced by proinflammatory cytokines, proatherogenic lipoproteins, and immune molecules. Furthermore, overexpression of SOCS suppressed STAT activation and reduced inflammatory gene expression and cell growth, whereas SOCS knockdown increased these cell responses. In vivo, antisense oligodeoxynucleotides targeting SOCS3 exacerbated the atherosclerotic process in apoE(-/-) mice by increasing the size, leukocyte content, and chemokine expression in the lesions. SOCS expressed in atherosclerotic lesions are key regulators of vascular cell responses. Activation of this endogenous antiinflammatory pathway might be of interest in the treatment of atherosclerosis.Arteriosclerosis Thrombosis and Vascular Biology 02/2009; 29(4):525-31. · 6.37 Impact Factor -
Article: Angiotensin-(1-7) and the g protein-coupled receptor MAS are key players in renal inflammation.
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ABSTRACT: Angiotensin (Ang) II mediates pathophysiologial changes in the kidney. Ang-(1-7) by interacting with the G protein-coupled receptor Mas may also have important biological activities.In this study, renal deficiency for Mas diminished renal damage in models of renal insufficiency as unilateral ureteral obstruction and ischemia/reperfusion injury while the infusion of Ang-(1-7) to wild-type mice pronounced the pathological outcome by aggravating the inflammatory response. Mas deficiency inhibited NF-kappaB activation and thus the elevation of inflammation-stimulating cytokines, while Ang-(1-7) infusion had proinflammatory properties in experimental models of renal failure as well as under basal conditions. The Ang-(1-7)-mediated NF-kappaB activation was Mas dependent but did not involve Ang II receptors. Therefore, the blockade of the NF-kappaB-activating properties of the receptor Mas could be a new strategy in the therapy of failing kidney.PLoS ONE 02/2009; 4(4):e5406. · 4.09 Impact Factor -
Article: Atorvastatin attenuates angiotensin II-induced inflammatory actions in the liver.
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ABSTRACT: Statins exert beneficial effects in chronically damaged tissues. Angiotensin II (ANG II) participates in liver fibrogenesis by inducing oxidative stress, inflammation, and transforming growth factor-beta1 (TGF-beta1) expression. We investigate whether atorvastatin modulates ANG II-induced pathogenic effects in the liver. Male Wistar rats were infused with saline or ANG II (100 ng kg(-1) min(-1)) for 4 wk through a subcutaneous osmotic pump. Rats received either vehicle or atorvastatin (5 mg kg(-1) day(-1)) by gavage. ANG II infusion resulted in infiltration of inflammatory cells (CD43 immunostaining), oxidative stress (4-hydroxynonenal), hepatic stellate cells (HSC) activation (smooth muscle alpha-actin), increased intercellular adhesion molecule (ICAM-1), and interleukin-6 hepatic gene expression (quantitative PCR). These effects were markedly blunted in rats receiving atorvastatin. The beneficial effects of atorvastatin were confirmed in an additional model of acute liver injury (carbon tetrachloride administration). We next explored whether the beneficial effects of atorvastatin on ANG II-induced actions are also reproduced at the cellular level. We studied HSC, a cell type with inflammatory and fibrogenic properties. ANG II (10(-8)M) stimulated cell proliferation, proinflammatory actions (NF-kappaB activation, ICAM-1 expression, interleukin-8 secretion) as well as expression of procollagen-alpha(1(I)) and TGF-beta1. All of these effects were reduced in the presence of atorvastatin (10(-7)M). These results indicate that atorvastatin attenuates the pathogenic events induced by ANG II in the liver both in vivo and in vitro. Therefore, statins could have beneficial effects in conditions characterized by hepatic inflammation.AJP Gastrointestinal and Liver Physiology 01/2009; 296(2):G147-56. · 3.43 Impact Factor -
Article: The MIF receptor CD74 in diabetic podocyte injury.
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ABSTRACT: Although metabolic derangement plays a central role in diabetic nephropathy, a better understanding of secondary mediators of injury may lead to new therapeutic strategies. Expression of macrophage migration inhibitory factor (MIF) is increased in experimental diabetic nephropathy, and increased tubulointerstitial mRNA expression of its receptor, CD74, has been observed in human diabetic nephropathy. Whether CD74 transduces MIF signals in podocytes, however, is unknown. Here, we found glomerular and tubulointerstitial CD74 mRNA expression to be increased in Pima Indians with type 2 diabetes and diabetic nephropathy. Immunohistochemistry confirmed the increased glomerular and tubular expression of CD74 in clinical and experimental diabetic nephropathy and localized glomerular CD74 to podocytes. In cultured human podocytes, CD74 was expressed at the cell surface, was upregulated by high concentrations of glucose and TNF-alpha, and was activated by MIF, leading to phosphorylation of extracellular signal-regulated kinase 1/2 and p38. High glucose also induced CD74 expression in a human proximal tubule cell line (HK2). In addition, MIF induced the expression of the inflammatory mediators TRAIL and monocyte chemoattractant protein 1 in podocytes and HK2 cells in a p38-dependent manner. These data suggest that CD74 acts as a receptor for MIF in podocytes and may play a role in the pathogenesis of diabetic nephropathy.Journal of the American Society of Nephrology 11/2008; 20(2):353-62. · 9.66 Impact Factor -
Article: Cluster TOF-SIMS imaging: a new light for in situ metabolomics?
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ABSTRACT: The advent of metal cluster as a primary ion source in the late 1980s, made it feasible to probe surfaces for complex organic structures due to a reduced in-source fragmentation, and opened the door to the direct analysis of biological samples. Despite the mass range measurable by TOF-secondary ion MS (SIMS) still being rather limited, the information obtained from cells and tissues comes together with the technical innovations introduced in the last decade. In this article, we give a brief overview of the technique itself and make some emphasis on the advances in the last three years in the analysis of biological surfaces, particularly those with direct implication in the biomedical field; reviewing what kind of information this instrumentation will add to current tool in pathology.Proteomics 09/2008; 8(18):3735-45. · 4.43 Impact Factor -
Article: Mechanisms of renal apoptosis in health and disease.
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ABSTRACT: Apoptotic cell death is usually a response to the cell microenvironment. Apoptosis requires the activation of lethal molecules and the inactivation of prosurvival ones. Both are potential therapeutic targets. Apoptosis contributes to parenchymal cell loss in the course of acute and chronic renal injury. Apoptotic pathways that are active in glomerular and tubular epithelium include death induced by survival factor deprivation, death receptor activation, mitochondrial injury, endoplasmic reticulum stress, lysosomal destabilization, and caspase cascade activation. These pathways are not mutually exclusive, and stimulus-specific differences in the recruitment of apoptotic pathways have been observed. In some cases, the activation of a certain death pathway is redundant, and its inhibition does not prevent eventual cell death. This review summarizes recent advances in the field and discusses the rational basis to choose from the available tools to target apoptosis therapeutically.Journal of the American Society of Nephrology 09/2008; 19(9):1634-42. · 9.66 Impact Factor -
Article: Proteomics in atherosclerosis.
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ABSTRACT: Atherothrombosis is the underlying cause of several clinical manifestations, such as acute coronary syndromes, cerebrovascular disease, and peripheral artery disease, which together are the leading cause of death in the Western world. Proteins from vascular cells or atherosclerotic plaques that are present in plasma are modified along the different steps of atherosclerotic development and constitute target candidates for vascular research, particularly in the search for novel biological markers of cardiovascular risk. In this review, we summarize proteomic techniques and the most recent results obtained by application of these high-throughput strategies to cardiovascular samples.Current Atherosclerosis Reports 07/2008; 10(3):209-15. · 2.66 Impact Factor -
Article: The death ligand TRAIL in diabetic nephropathy.
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ABSTRACT: Apoptotic cell death contributes to diabetic nephropathy (DN), but its role is not well understood. The tubulointerstitium from DN biopsy specimens was microdissected, and expression profiles of genes related to apoptosis were analyzed. A total of 112 (25%) of 455 cell death-related genes were found to be significantly differentially regulated. Among those that showed the greatest changes in regulation were two death receptors, OPG (the gene encoding osteoprotegerin) and Fas, and the death ligand TRAIL. Glomerular and proximal tubular TRAIL expression, assessed by immunohistochemistry, was higher in DN kidneys than controls and was associated with clinical and histologic severity of disease. In vitro, proinflammatory cytokines but not glucose alone regulated TRAIL expression in the human proximal tubular cell line HK-2. TRAIL induced tubular cell apoptosis in a dosage-dependant manner, an effect that was more marked in the presence of high levels of glucose and proinflammatory cytokines. TRAIL also activated NF-kappaB, and inhibition of NF-kappaB sensitized cells to TRAIL-induced apoptosis. It is proposed that TRAIL-induced cell death could play an important role in the progression of human DN.Journal of the American Society of Nephrology 06/2008; 19(5):904-14. · 9.66 Impact Factor -
Article: TWEAKing renal injury.
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ABSTRACT: TWEAK is a recently identified cytokine of the TNF superfamiliy. Through activation of the Fn14 receptor, TWEAK regulates cell proliferation, cell death and inflammation. Recent studies show increased TWEAK and Fn14 expression in tubular cells during acute kidney injury as well as elevated urinary TWEAK levels in patients with active lupus nephritis. Furthermore, glomerular mesangial cells and renal tubular epithelial cells express the Fn14 receptor under the regulation of proinflammatory cytokines. TWEAK weakly increases cell death and promotes secretion of inflammatory mediators in non-stimulated mesangial cells. In addition, in a proinflammatory milieu, TWEAK induces apoptosis of mesangial and tubular cells. The available data suggest that TWEAK is a new player in kidney injury both at the glomerular and tubulointerstitial levels and might be a target for therapeutic intervention.Frontiers in Bioscience 02/2008; 13:580-9. · 3.52 Impact Factor -
Article: A slit in podocyte death.
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ABSTRACT: Recent advances have identified the podocyte as a key target in glomerular injury. The podocyte is a highly specialized cell which is responsible for the glomerular permselectivity for proteins in the kidney. Podocyte injury or loss leads to proteinuria. Apoptosis has been shown to contribute to renal cell loss, including loss of podocytes. The most striking feature of the podocyte is its ability to form intricate specialized cell junctions, the slit diaphragm. Slit diaphragm proteins play an important role in podocyte biology, protein permselectivity, cell signalling and disease. This review focuses on recent advances on the understanding of podocyte survival regulation, its relationship to slit diaphragm structure and function, and how this knowledge may affect our therapeutic approach to proteinuric kidney disease.Current Medicinal Chemistry 02/2008; 15(16):1645-54. · 4.86 Impact Factor -
Article: The chronic intake of a Mediterranean diet enriched in virgin olive oil, decreases nuclear transcription factor kappaB activation in peripheral blood mononuclear cells from healthy men.
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ABSTRACT: Nuclear transcription factor kappaB (NF-kappaB) plays a key role in the inflammatory response and can be modulate by dietary fat. We have examined the effect of three diets, with different fat composition, on the activation of NF-kappaB on peripheral blood mononuclear cells (PBMCs). Sixteen healthy men followed three 4-week diets, in a randomised crossover design: a Western diet, rich in saturated fat (SFA) [22% SFA, 12% monounsaturated fat (MUFA) and 0, 4 alpha-linolenic acid]; a Mediterranean diet [<10% SFA, 24% MUFA and 0.4% alpha-linolenic acid], and a low fat diet enriched in alpha-linolenic acid [<10% SFA, 12% MUFA and 2% alpha-linolenic acid]. NF-kappaB (electrophoretic mobility shift assay) in mononuclear cells and plasma concentrations (ELISA) of soluble vascular cellular adhesion molecule 1 (VCAM-1) were examined after either diets. Western diet increased 2.7-fold NF-kappaB compared with the Mediterranean diet (p=0.038) and 1.79-fold with the alpha-linolenic acid diet (p=0.07). No differences were found between the last two. Furthermore, an increase on plasma VCAM-1 was observed with the Western diet (p<0.05). The Mediterranean diet diminished NF-kappaB activation in mononuclear cells, compared with Western diet, supporting its cardioprotective properties. The effect of the n-3 enriched diet was intermediate.Atherosclerosis 11/2007; 194(2):e141-6. · 3.79 Impact Factor -
Article: Anti-inflammatory actions of quinapril.
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ABSTRACT: OBJECTIVE: The role of angiotensin II (Ang-II) in inflammation and the mechanisms through which it exerts this role are explored. Signaling through angiotensin stimulation of inflammatory cells often amplifies inflammation. Formation of Ang-II from tissue angiotensin-converting enzyme (ACE) has been shown to be of greater importance in the development and progression of inflammatory diseases than plasma ACE. CONCLUSION: Quinapril, which is a potent and selective inhibitor of both plasma and tissue ACE, has demonstrated anti-inflammatory properties in many disease states such as atherosclerosis, nephritis, scleroderma, diabetes and arthritis, and, thus, offers new therapeutic possibilities for disease treatment.Cardiovascular Drugs and Therapy 06/2007; 21(3):211-20. · 3.13 Impact Factor -
Article: Proteomics in atherothrombosis: a future perspective.
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ABSTRACT: Atherothrombosis is the primary cause of death in Western countries. The cellular and molecular mechanisms underlying atherosclerosis remain widely unknown. The complex nature of atherosclerotic cardiovascular diseases demands the development of novel technologies that enable discovery of new biomarkers for early disease detection and risk stratification, which may predict clinical outcome. In this review, we outline potential sources and recent proteomic approaches that could be applied in the search of novel biomarkers of cardiovascular risk. In addition, we describe some issues raised in relation to the application of proteomics to blood samples, as well as two novel emerging concepts, such as peptidomics and population proteomics. In the future, the use of high-throughput techniques (proteomic, genomics and metabolomics) will potentially identify novel patterns of biomarkers, which, along with traditional risk factors and imaging techniques, could help to target vulnerable patients and monitor the beneficial effects of pharmacological agents.Expert Review of Proteomics 04/2007; 4(2):249-60. · 3.68 Impact Factor -
Article: TWEAK and Fn14. New players in the pathogenesis of atherosclerosis.
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ABSTRACT: Atherosclerosis is currently described as an inflammatory disease given that the main components of chronic inflammation are present in this process: cell recruitment, proliferation, neovascularization, and sclerosis. Vascular lesions are caused by inflammatory and fibroproliferative responses to injury of the endothelium and vascular smooth muscle cells. Interaction between members of the tumor necrosis factor (TNF) superfamily and their receptors elicits diverse biologic actions that participate in atherosclerosis development. These responses include the expression of adhesion molecules, proinflammatory cytokines, matrix metalloproteinases, and tissue factor, which are known to increase plaque instability. TNF-like weak inducer of apoptosis (TWEAK) is a recently described member of the TNF superfamiliy, which is involved in induction of inflammation, activation of cell growth, and stimulation of apoptosis. In this review, we summarize the potential proatherogenic consequences of the interaction of TWEAK with its receptor Fn14 in the vascular wall.Frontiers in Bioscience 02/2007; 12:3648-55. · 3.52 Impact Factor -
Article: Trail and vascular injury.
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ABSTRACT: Cardiovascular diseases are the leading cause of mortality in the Western world. The underlying pathological process is a thickening of the arterial wall due to the formation of atheromatous plaques which contain a lipid core covered by a fibrous cap. The main mechanisms involved in atherogenesis are: lipoprotein retention, endothelial cell activation, vascular smooth muscle cell proliferation, macrophage infiltration, proteolytic injury, neovascularization and apoptosis. Different members of the tumor necrosis factor family (TNF) of proteins have been detected in human atherosclerotic plaques, among these are TNF-related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-Rs and osteoprotegerin, OPG). In this review, the involvement of TRAIL and its receptors in the mechanisms underlying atherothrombosis is reviewed. In this respect, there are still some controversial data on the effects of TRAIL on inflammation and apoptosis of vascular cells. However, recent in vivo studies have suggested a potential proinflammatory and proapoptotic role of TRAIL in vascular injury. In addition, soluble forms of the TNF-superfamily can be released extracellularly and have been detected in human plasma. For this reason, we different studies evaluating the potential use of TRAIL and OPG plasma levels as markers of vascular injury are discussed.Frontiers in Bioscience 02/2007; 12:3656-67. · 3.52 Impact Factor -
Article: Proteomic analysis of early left ventricular hypertrophy secondary to hypertension: modulation by antihypertensive therapies.
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ABSTRACT: Untreated or poorly controlled arterial hypertension induced development of pathologic left ventricular hypertrophy (LVH), a common finding in hypertensive patients and a strong predictor of cardiovascular morbidity and mortality. The proteomic approach is a powerful technique to analyze a complex mixture of proteins in various settings. An experimental model of hypertension-induced early LVH was performed in spontaneously hypertensive rats, and the cardiac protein pattern compared with the normotensive Wistar Kyoto counterpart was analyzed. Fifteen altered protein spots were shown in the early stage of LVH. Compared with a previous animal model of established and regressed LVH, three protein spots were common in both models. These three altered protein spots corresponded to two unique proteins that were identified as Calsarcin-1 (CS-1) and ubiquinone biosynthesis protein COQ7 homolog. CS-1 is a negative regulator of the calcineurin/NF-AT pathway. Because upregulation in the expression levels of this protein was observed, the activation level of NF-kappaB by oxidative stress as an alternative pathway was investigated. It was found that antihypertensive therapies partially decreased oxidative stress and normalized the activation of NF-kappaB in the kidneys and aorta NF-kappaB activation but just moderately in the heart. This could be due to the interaction of any specific cardiac protein with any component of the NF-kappaB pathway. In this sense, CS-1 could be a good candidate because it is expressed preferentially in heart, to a lesser extent in smooth muscle cells, but not in kidney. Further investigations are necessary to elucidate the exact role of CS-1 and ubiquinone biosynthesis protein COQ7 in the setting of hypertension-induced LVH.Journal of the American Society of Nephrology 01/2007; 17(12 Suppl 3):S159-64. · 9.66 Impact Factor -
Article: Role of connective tissue growth factor in vascular and renal damage associated with hypertension in rats. Interactions with angiotensin II.
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ABSTRACT: We have evaluated the role of connective tissue growth factor (CTGF) in vascular and renal damage associated with hypertension and possible interactions with angiotensin II (Ang II). Spontaneously hypertensive rats (SHR) were treated with either the Ang II receptor antagonist candesartan (C;2 mg/Kg(-1)/day(-1)) or antihypertensive triple therapy (TT; in mg/Kg(-1)/day(-1);20 hydralazine +7 hydrochlorothiazide +0.15 reserpine) for 10 weeks. Wistar Kyoto rats were used as a normotensive control group. Hypertension was associated with an increase in aortic media area, media-to-lumen ratio and collagen density. Kidneys from SHR showed minimum renal alterations. Aorta and renal gene expression and immunostaining of CTGF were higher in SHR. Candesartan decreased arterial pressure, aortic media area, media-to-lumen ratio and collagen density. However, although arterial pressure decrease was comparable for both treatments, TT partially reduced these parameters. Candesartan-treated rats showed lower levels of vascular CTGF expression, aortic media area, media-to-lumen ratio and collagen density than TT-treated animals. Treatments improve renal damage and reduce renal gene expression and CTGF immunostaining in SHR in a similar manner. The results show that vascular and renal damage is associated with stimulation of CTGF gene and protein content. These results also might suggest that CTGF could be one downstream mediator of Ang II in hypertension-associated organ damage in SHR.Journal of Renin-Angiotensin-Aldosterone System 01/2007; 7(4):192-200. · 2.44 Impact Factor -
Article: Comparison of the protein profile of established and regressed hypertension-induced left ventricular hypertrophy.
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ABSTRACT: Established left ventricular hypertrophy (LVH) showed a significant alteration in the cardiac protein profile compared with normal heart. The main finding of this work was to identify proteins differently expressed in hypertension-induced LVH and the fact that after regression of LVH (histologically determined), the proteome still maintains a number of expressed proteins characteristic of the hypertrophied heart. These unrecovered proteins play an essential role in the energy production pathway, in cellular stress defense and also in hypertrophy regulation.Journal of Proteome Research 03/2006; 5(2):404-13. · 5.11 Impact Factor -
Article: Proteomic approach in the search of new cardiovascular biomarkers.
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ABSTRACT: With the increasing incidence of cardiovascular diseases worldwide, specifically atherosclerosis and heart failure, the search for novel biomarkers remains a priority. As opposed to complex diagnostic techniques that may not be suitable to be applied to the wider population, biomarkers are useful for population screening. The search for novel biomarkers is based on knowledge of the molecular and cellular processes that take place in the development of a specific disease. Atherosclerosis and heart failure are characterized by a long period of silent disease progression, allowing early diagnosis and the potential of early therapeutic intervention. The use of the so-called proteomic techniques allows not only protein identification but partial characterization, which includes expression and also post-translational modification of these proteins. This allows for the discovery of previously unknown proteins involved in cardiovascular diseases, including some that may be suitable to be used as biomarkers. However, to approach this issue, we have to overcome difficulties such as tissue heterogeneity (vessel wall or myocardium) and the lack of fresh human samples. We discuss the proteomic study of human plaques, secreted proteins by pathologic and normal vessel wall, and left ventricular hypertrophy as potential sources of new biologic markers of cardiovascular disease.Kidney international. Supplement 01/2006; -
Article: HMG-CoA reductase inhibitors reduce I kappa B kinase activity induced by oxidative stress in monocytes and vascular smooth muscle cells.
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ABSTRACT: Reactive oxygen species, such as superoxide anion (O2-) and hydrogen peroxide (H2O2), may act as second messengers of intracellular signaling and play a key role in the pathogenesis of atherosclerosis. The nuclear factor kappaB (NF-kappa B) is a redox-sensitive transcription factor that is involved in this process. The aim of the present study was to investigate the molecular mechanisms of action of statins on cultured vascular smooth muscle cells (VSMC) and monocytic cells (THP-1) under oxidative stress. In THP-1 and cultured VSMC, O2- caused an increase in NF-kappa B activation (P < 0.05) that was correlated with inhibitory I kappa B-alpha degradation. Atorvastatin or simvastatin decreased NF-kappa B activation induced by oxidative stress by around 50% in both cell types and was correlated with the I kappa B-alpha levels. In monocytes, O2- increased I kappa B kinase (IKK)-1 and IKK-2 activity (P < 0.05) and p38 and p42/44 activation and phosphorylation, which was reduced by statins. PD 98059 (p42/44 inhibitor) and SB20358 (p38 inhibitor) decreased NF-kappa B binding activity and prevented I kappa B-alpha degradation. However, we only observed a reduction in IKK-1 and IKK-2 activity with PD98059. Statins diminish NF-kappa B activation elicited by oxidative stress through the inhibition of IKK-1/-2, p38, and p42/44 activation. These data may help to further understand the molecular mechanisms of statins in cardiovascular disease.Journal of Cardiovascular Pharmacology 05/2005; 45(5):468-75. · 2.29 Impact Factor
Top co-authors
Top Journals
Institutions
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2002–2013
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Universidad Autónoma de Madrid
- Enfermería de la Fundación Jiménez Díaz
Madrid, Madrid, Spain
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2004–2012
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Fundación Jiménez Díaz
Madrid, Madrid, Spain
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2011
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Spanish National Centre for Cardiovascular Research
Madrid, Madrid, Spain
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2006–2009
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Hospital General Universitario Gregorio Marañón
- Department of Cardiology
Madrid, Madrid, Spain
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