Genetic deletion or TWEAK blocking antibody administration reduce atherosclerosis and enhance plaque stability in mice.

Clinical complications associated with atherosclerotic plaques arise from luminal obstruction due to plaque growth or destabilization leading to rupture. Tumour necrosis factor ligand superfamily member 12 (TNFSF12) also known as TNF-related weak inducer of apoptosis (TWEAK) is a proinflammatory cytokine that participates in atherosclerotic plaque development, but its role in plaque stability remains unclear. Using two different approaches, genetic deletion of TNFSF12 and treatment with a TWEAK blocking mAb in atherosclerosis-prone mice, we have analysed the effect of TWEAK inhibition on atherosclerotic plaques progression and stability.

Indomethacin Prevents the Progression of Thoracic Aortic Aneurysm in Marfan Syndrome Mice.

Background: Marfan syndrome (MFS), an inherited disorder of connective tissue characterized by abnormalities in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the gene for fibrillin-1 (FBN1). The high mortality in untreated patients is primarily due to aneurysm and dissection of the ascending aorta. The complex pathogenesis of MFS involves changes in transforming growth factor β (TGF-β) signaling, increased matrix metalloproteinase (MMP) expression, and fragmentation of the extracellular matrix.

HMGB1 expression and secretion are increased via TWEAK-Fn14 interaction in atherosclerotic plaques and cultured monocytes.

Objective: High-mobility group box 1 (HMGB1), a DNA-binding cytokine expressed mainly by macrophages, contributes to lesion progression and chronic inflammation within atherosclerotic plaque. It has been suggested that different cytokines could regulate HMGB1 expression in monocytes. We have analyzed the effect of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) on HMGB1 expression both in vivo and in vitro.

Antagonism of GxxPG fragments ameliorates manifestations of aortic disease in Marfan syndrome mice.

Marfan syndrome (MFS) is an inherited disorder of connective tissue caused by mutations in the gene for fibrillin-1 (FBN1). The complex pathogenesis of MFS involves changes in transforming growth factor beta (TGF-β) signaling and increased matrix metalloproteinase (MMP) expression. Fibrillin-1 and elastin have repeated Gly-x-x- Pro-Gly (GxxPG) motifs that can induce a number of effects including macrophage chemotaxis and increased MMP activity by induction of signaling through the elastin-binding protein (EBP).

HSP90 inhibition by 17-DMAG attenuates oxidative stress in experimental atherosclerosis.

Aims: Reactive oxygen species (ROS) participate in atherogenesis through different mechanisms including oxidative stress and inflammation. Proteins implicated in both processes, such as mitogen-activated protein kinase kinase (MEK) and some NADPH oxidase (NOX) subunits, are heat shock protein-90 (HSP90) client proteins. In this work, we investigated the antioxidant properties of the HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in experimental atherosclerosis.

TWEAK-Fn14 interaction enhances plasminogen activator inhibitor 1 and tissue factor expression in atherosclerotic plaques and in cultured vascular smooth muscle cells.

Aims: atherosclerotic plaque development can conclude with a thrombotic acute event triggered by plaque rupture/erosion. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumour necrosis factor superfamily that, through its receptor, fibroblast growth factor-inducible 14 (Fn14), participates in vascular remodelling, increasing vascular inflammatory responses and atherosclerotic lesion size in ApoE knockout mice. However, the role of the TWEAK-Fn14 axis in thrombosis has not been previously investigated.

Heat shock protein 90 inhibitors attenuate inflammatory responses in atherosclerosis.

Aims: Heat shock protein 90 (HSP90) is a ubiquitous chaperone involved in the folding, activation, and assembly of many proteins. HSP90 inhibitors [17-allylamino-17-demethoxygeldamycin (17-AAG)/17-dimethyl aminothylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG)] bind to and inactivate HSP90, increasing the heat shock response and suppressing different signalling pathways. We aim to investigate the effect of HSP90 inhibitors in the modulation of inflammatory responses during atherogenesis.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) enhances vascular and renal damage induced by hyperlipidemic diet in ApoE-knockout mice.

Objective: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of cytokines. TWEAK binds and activates the Fn14 receptor, and may regulate apoptosis, inflammation, and angiogenesis, in different pathological conditions. We have evaluated the effect of exogenous TWEAK administration as well as the role of endogenous TWEAK on proinflammatory cytokine expression and vascular and renal injury severity in hyperlipidemic ApoE-knockout mice.

Considering TWEAK as a target for therapy in renal and vascular injury.

TWEAK is a cytokine of the TNF superfamily that activates the Fn14 receptor. TWEAK may regulate cell proliferation, cell death, cell differentiation, angiogenesis and inflammation. The expression of TWEAK and Fn14 is increased during vascular and renal injury.

Biomarkers in cardiovascular medicine.

Cardiovascular disease is the principal cause of death in developed countries. The underlying pathological process is arterial wall thickening due to the formation of atherosclerotic plaque, which is frequently complicated by thrombus, thereby giving rise to the possibility of acute coronary syndrome or stroke. One of the major challenges in cardiovascular medicine is to find a way of predicting the risk that an individual will suffer an acute thrombotic event.

The CD163-expressing macrophages recognize and internalize TWEAK: potential consequences in atherosclerosis.

Background: CD163 is a new potential scavenger receptor of Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) which elicits diverse biologic actions involved in atherosclerosis. We have analyzed the importance of TWEAK-CD163 interaction in atherosclerosis.

Methods: TWEAK and CD163 interaction was studied in cultured human macrophages.

Increased CD74 expression in human atherosclerotic plaques: contribution to inflammatory responses in vascular cells.

Aims: The purpose of this study was to analyse the expression of CD74 in human atherosclerotic plaques and peripheral blood mononuclear cells (PBMC) as well as its potential participation in proinflammatory responses in cultured human vascular smooth muscle cells (VSMC).

Methods And Results: CD74 expression was analysed in human atherosclerotic plaques (immunohistochemistry), PBMC (real-time PCR), and human aortic VSMC (real-time PCR and western blotting). Nuclear factor-kappaB (NF-kappaB) activation was assessed by southwestern histochemistry and electrophoretic mobility shift assay.

Suppressors of cytokine signaling modulate JAK/STAT-mediated cell responses during atherosclerosis.

Objective: 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.

Methods And Results: 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.

Treatment with amlodipine and atorvastatin has additive effect on blood and plaque inflammation in hypertensive patients with carotid atherosclerosis.

Since previous studies have reported a beneficial effect of amlodipine and atorvastatin treatment in experimental atherosclerosis, we aimed to investigate the effect of the combination of both drugs on blood and plaque inflammation in patients with carotid stenosis. For that purpose, twenty six hypertensive patients undergoing carotid endarterectomy were randomized to receive either atorvastatin 20 mg/day alone (ATV, n=12) or in combination with amlodipine 20 mg/day (ATV+AML, n=14) before scheduled carotid endarterectomy. At the end of follow-up (4-6 weeks), there was a significant decrease in total and LDL-cholesterol levels, but not in blood pressure levels.

Leukotriene B4 enhances the activity of nuclear factor-kappaB pathway through BLT1 and BLT2 receptors in atherosclerosis.

Aims: Leukotriene B4 (LTB4) is a powerful chemoattractant and pro-inflammatory mediator in several inflammatory diseases, including atherosclerosis. It acts through its two membrane receptors, BLT1 and BLT2. The aim of this study was to determine the molecular mechanism involved in the proatherogenic effect of LTB4, BLT1 and BLT2 in atherosclerosis.

Trail and vascular injury.

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.

TWEAK and Fn14. New players in the pathogenesis of atherosclerosis.

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.

Identification of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) as a possible biomarker of subclinical atherosclerosis.

Objectives: Assessment of vascular risk in asymptomatic patients and the response to medical therapy is a major challenge for prevention of cardiovascular events. Our aim was to identify proteins differentially released by healthy versus atherosclerotic arterial walls, which could be found in plasma and serve as markers of atherosclerosis.

Methods And Results: We have analyzed supernatants obtained from cultured human carotid plaques and healthy arteries by surface-enhanced laser-desorption/ionization time-of-flight mass spectrometry ProteinChip System.

Ethanol beverages containing polyphenols decrease nuclear factor kappa-B activation in mononuclear cells and circulating MCP-1 concentrations in healthy volunteers during a fat-enriched diet.

Aims: Different epidemiological studies have demonstrated that some ethanol containing beverages intake could be associated with a reduction of cardiovascular mortality, effect attributed in part to its antioxidant properties. Nuclear factor-kappa B (NF-kappaB) is a redox sensitive transcription factor implicated in the pathogenesis of atherosclerosis. We have examined the effect of four different ethanol containing beverages on the activation of NF-kappaB in peripheral blood mononuclear cells (PBMC) and circulating concentrations of monocyte chemoattractant protein-1 (MCP-1) in healthy volunteers receiving a fat-enriched diet.

Fn14 is upregulated in cytokine-stimulated vascular smooth muscle cells and is expressed in human carotid atherosclerotic plaques: modulation by atorvastatin.

Background And Purpose: Interaction between different members of the tumor necrosis factor superfamily and their receptors elicits diverse biologic actions that are implicated in the pathogenesis of atherosclerosis. We have analyzed the expression of Fn14 and its ligand TWEAK in carotid atherosclerotic plaques and its potential modulation by atorvastatin in vivo. Furthermore, we have studied whether proinflammatory cytokines regulate Fn14 expression in human aortic smooth muscle cells (hASMCs) in culture as well as the potential regulation by atorvastatin treatment.

Intensive treatment with atorvastatin reduces inflammation in mononuclear cells and human atherosclerotic lesions in one month.

Background And Purpose: To investigate the effect of short-term high-dose atorvastatin on blood and plaque inflammation in patients with carotid stenosis.

Methods: Twenty patients undergoing carotid endarterectomy without previous statin treatment were randomized to receive either atorvastatin 80 mg/d (n=11) or no statins (n=9) for 1 month. We studied inflammatory mediators in plasma (enzyme-linked immunosorbent assay), peripheral blood mononuclear cells (PBMCs; quantitative RT-PCR and EMSA) and plaques (immunohistochemistry and Southwestern histochemistry).

NF-kappaB activation and Fas ligand overexpression in blood and plaques of patients with carotid atherosclerosis: potential implication in plaque instability.

Background And Purpose: Apoptosis is present in human atherosclerotic lesions. Nuclear factor-kappaB (NF-kappaB) is involved in the transcriptional regulation of the proapoptotic protein Fas ligand (FasL). We have analyzed NF-kappaB activation and FasL expression in atherosclerotic plaques and peripheral blood mononuclear cells (PBMCs) of patients with carotid stenosis.

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors decrease Fas ligand expression and cytotoxicity in activated human T lymphocytes.

Background: HMG-CoA reductase inhibitors reduce cardiovascular mortality, although the mechanisms of action have not been completely elucidated. The presence of T cells and apoptotic cells in atherosclerotic plaques is well established, the reduction of cellular content being a marker of their vulnerability. One of the main mechanisms of cell death activation is the Fas-Fas ligand (FasL) system.