Anti-inflammatory and immunomodulatory effects of statins. 3-Hydroxy-3-methyl-gutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins constitute the most powerful class of lipid-lowering drugs. Clinical trials have demonstrated a marked reduction in cardiovascular mortality in patients treated with statins. However, the benefits observed with statin therapy appear to be related, at least in part, with their cholesterol-lowering independent effects. Extensive research carried out mainly in the last decade suggests that the clinical benefits of these drugs could be related to an improvement in endothelial dysfunction, a reduction in blood thrombogenicity, anti-inflammatory properties, and, recently, immunomodulatory actions. In this sense, statins decrease T cell activation, the recruitment of monocytes and T cells into the arterial wall, and enhance the stability of atherosclerotic lesions. Many of these effects are related with the inhibition of isoprenoid synthesis, which serve as a lipid attachment for a variety of proteins implicated in intracellular signaling. In fact, small G proteins, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in the lipid-lowering independent effects of HMG-CoA reductase inhibitors. This article summarizes the anti-inflammatory and immunomodulatory effects of statins and their participation in the different steps of atherosclerotic lesion formation.

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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. Methods and Results-ApoEϪ/Ϫ mice were fed with hyperlipidemic diet for 4 to 10 weeks, then randomized and treated with saline (controls), TWEAK (10 g/kg/d), anti-TWEAK neutralizing mAb (1000 g/kg/d), TWEAK plus anti-TWEAK antibody (10 g TWEAK ϩ1000 g anti-TWEAK/kg/d), or nonspecific IgG (1000 g/kg/d) daily for 9 days. In ApoE Ϫ/Ϫ mice, exogenous TWEAK administration in ApoE Ϫ/Ϫ mice induced activation of NF-B, a key transcription factor implicated in the regulation of the inflammatory response, in vascular and renal lesions. Furthermore, TWEAK treatment increased chemokine expression (RANTES and MCP-1), as well as macrophage infiltration in atherosclerotic plaques and renal lesions. These effects were associated with exacerbation of vascular and renal damage. Conversely, treatment of ApoE Ϫ/Ϫ mice with an anti-TWEAK blocking mAb decreased NF-B activation, proinflammatory cytokine expression, macrophage infiltration, and vascular and renal injury severity, indicating a pathological role for endogenous TWEAK. Key Words: Inflammation Ⅲ atherosclerosis Ⅲ kidney Ⅲ hyperlipidemia Ⅲ TWEAK A therosclerosis 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. 1 Vascular lesions are caused by inflammatory and fibroproliferative responses to injury of the endothelium and vascular smooth muscle cells (VSMCs). Interaction between members of the tumor necrosis factor (TNF) superfamily and their receptors elicits diverse biological 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. One of these members is the TNF-like weak inducer of apoptosis (TWEAK/TNFS12), which has different biological functions, including induction of inflammation, angiogenesis, activation of cell growth, and stimulation of apoptosis. [2][3] The receptor of this protein is TWEAKR/Fn14, the smallest reported member of the TNF superfamily. 4 TWEAK and Fn14 are expressed in different cell types, including endothelial and VSMCs. 5 In addition, TWEAK/Fn14 interaction induces the secretion of proinflammatory chemokines such as interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in different cell types. 2-3 Both TWEAK and Fn14 have been detected in the diseased vessel wall, implicating this pathway in atherosclerotic plaque ...

Background and objectives: Chronic kidney disease (CKD) is characterized by an exceptionally high mortality rate, primarily due to cardiovascular disease. Reduced soluble TNF-like weak inducer of apoptosis (sTWEAK) plasma levels have been reported both in patients with subclinical atherosclerosis and CKD.Design, participants, & measurements: A cross-sectional study was conducted in 218 prevalent patients (121 men; 63 ؎ 14 yr) undergoing hemodialysis (HD). sTWEAK levels in relation with the patients' outcome were studied.Results: sTWEAK plasma levels were 208 [(165 to 272) pg/ml, median interquartile range], significantly lower than healthy controls (P < 0.0001). sTWEAK was negatively associated with inflammatory markers, such as C-reactive protein and IL-6. Overall mortality was assessed after an average follow-up of 31 mo, during which 81 patients died. After controlling for potential confounding variables, patients in the upper tertile of sTWEAK plasma levels had an increased risk of cardiovascular and all-cause mortality. A significant interaction effect between sTWEAK and IL-6 levels was found [synergy index: 2.19 (0.80, 5.93)]. Thus, the association of sTWEAK with mortality was strongest in patients with inflammation (defined as IL-6 > 7.0 pg/ml), in whom high sTWEAK strongly predicted cardiovascular and all-cause mortality. These results were confirmed in a second cohort of HD patients.Conclusions: The concurrent presence of elevated sTWEAK plasma concentrations and an inflammatory environment have additive effects on mortality in HD patients. Further studies on the potential different role of sTWEAK in health and disease are warranted.

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. Surfaceenhanced laser-desorption/ionization analysis unveiled an 18.4-kDa peak released in lower amount by carotid plaques than normal endarteries. This protein was identified as soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK). To confirm that sTWEAK was the protein of interest, Western blot and enzyme-linked immunosorbent assay were performed. Both techniques confirmed that sTWEAK levels were decreased in carotid plaque supernatants. Subsequent measurement of sTWEAK in plasma showed a reduced concentration in subjects with carotid stenosis (Nϭ30) compared with healthy subjects matched by sex and age (Nϭ28) 1 Atherogenesis is a complex process characterized by lipid deposition and a chronic inflammatory response. The resulting pathological vascular remodeling involves inflammatory cell recruitment, fibrosis, smooth muscle cell proliferation, and neovascularization. 2 Our hypothesis is that atherosclerotic plaque prone to rupture could display a particular profile of released proteins, reflecting directly the late events preceding rupture such as proteolysis or cell death. The levels of several inflammatory molecules in circulating blood have been shown to be elevated in subjects at risk for an acute coronary event. [3][4] Most of existing markers were proposed based on the assessment of proteins in plasma related to inflammation process associated with atherosclerosis (eg, C-reactive protein, CD40 ligand). 5 We have recently reported a new strategy to identify potential biological markers directly released by the arterial wall, using a proteomic approach. 6 -7 Incubation of endarterectomy samples versus control endarteries in a serum-free culture medium allowed us to harvest separately the proteins released from pathological and healthy areas and the supernatants (conditioned media) were subsequently analyzed by 2-dimensional electrophoresis. After identification of the differentially released proteins, their levels are measured in plasma to assess their potential as biomarkers of atherosclerosis. In this article, using a similar approach, we have analyzed the conditioned media from normal mammary endarteries versus carotid atherosclerotic endarterectomy samples by surface-enhanced laser desorption ionization (SELDI) time-of-flight (TOF) mass spectrometry (MS). This method is based on the chromatographic fractionation of the proteome on ProteinChips before MS analysis; it allows an easy and quantitative comparison of profiles of proteins relea...

Consumption of an olive oil-enriched meal does not activate NF-kappaB in monocytes as do butter and walnut-enriched meals. This effect could enhance the cardioprotective effect of olive oil-enriched diets.

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. Methods-Fn14 and TWEAK expression was analyzed in human carotid atherosclerotic plaques. Furthermore, Fn14 expression was studied in hASMCs in culture. Results-Fn14 and TWEAK are expressed in macrophages and smooth muscle cells in carotid atherosclerotic plaques.Proinflammatory cytokines (interleukin-1␤ and interferon-␥) upregulate Fn14 expression in hASMCs. This effect was prevented by atorvastatin treatment and reversed by mevalonate and geranylgeranyl pyrophosphate. Geranylgeranyl transferase inhibitor, toxin B (Rac and Rho inhibitor), C3 exoenzyme (Rho inhibitor), and Y-27632 (Rho kinase inhibitor) also decreased Fn14 expression, implicating the Rho/Rho kinase pathway in the regulation of Fn14 expression. Finally, atorvastatin treatment reduced Fn14 expression in vivo. Conclusions-TWEAK and Fn14 are expressed in atherosclerotic plaques and could be novel mediators of atherosclerosis.Atorvastatin diminishes Fn14 expression in vitro and in vivo providing novel information of the beneficial properties of statins.

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