Statins as Pleiotropic Modifiers of Vascular Oxidative Stress and Inflammation (original) (raw)
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Effects of statins on adhesion molecule expression in endothelial cells
Journal of Thrombosis and Haemostasis, 2003
Background: Inhibitors of HMG-CoA reductase are widely used to prevent atherosclerosis progression. The expression of adhesion molecules on activated endothelial cells (EC) is an important step in the initiation and progression of atherosclerosis. Objectives: We investigated whether adhesion molecule expression on activated EC is in¯uenced by simvastatin,¯uvastatin and pravastatin and, if so, by which mechanisms. Methods: Human EC from umbilical veins or saphenous veins were pretreated overnight with statins with or without mevalonate, and also for simvastatin or¯uvastatin with the isoprenoid intermediates, farnesyl pyrophosphate (FPP), or geranylgeranyl pyrophosphate (GGPP). After 4±6 h activation with tumor necrosis factor (TNF)-a or lipopolysaccharide (LPS), surface adhesion molecule expression was evaluated by ELISA and by¯ow cytometry. The same experiments were performed with selective inhibitors of geranylgeranyltransferase (GGTI-286) and farnesyltransferase (FTI-277). Results: Pretreatment with simvastatin,¯uvastatin or pravastatin potentiated the TNF-a and LPS-induced expression of E-selectin and VCAM-1, and mevalonate reversed the potentiating effect of these statins. GGPP also reversed the potentiating effect of simvastatin or¯uvastatin on adhesion molecule expression, while FPP only partially reversed this effect. Furthermore, GGTI-286, but not FTI-277, mimicked the effect of simvastatin by increasing the TNF-a-mediated overexpression of E-selectin. Conclusions: Statins increase E-selectin-and VCAM-1-induced expression on vascular endothelial cells stimulated with TNF-a or LPS. The inhibition of geranylgeranylated proteins could contribute to this effect.
Atherosclerosis, 2009
Statins have been demonstrated to significantly affect the prognosis and outcome of patients with risk factors to atherosclerosis (in primary and secondary prevention trials). Several clinical and recently basic studies have suggested an extra-beneficial effect of the statins in the prevention of atherosclerosis and coronary artery disease. These studies showed that statins may affect the cardiovascular system beyond their effect on the lipid profile, and it was suggested that they affect the immunological system and vascular inflammation. Many of the beneficial pleiotropic effects of statins occur as a result of modulated endothelial function and reduced inflammatory processes. Attempting to understand these properties of statins is an exciting field of research that will also improve our understanding of vascular biology in health and disease, and thus enable the better use of this drug class in clinical practice.
Journal of Pharmacology and Toxicology, 2023
Atherosclerosis and its complications represent the major cause of death in developed countries. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A [HMGCoA] reductase and consequently inhibitors of cholesterol biosynthesis. Statins have been described as the most potent class of drugs to reduce serum cholesterol levels. In clinical trials, statins are beneficial in primary and secondary prevention of coronary heart disease. Statins, were initially designed as cholesterol-lowering drugs. However, these drugs, besides their lipid-lowering properties, exert a number of protective effects on the cardiovascular system that emerged over the past years. The benefits observed with statin treatment appear to be greater than that might be expected from reduction in lipid levels alone, suggesting effects beyond cholesterol lowering. These cholesterol-independent effects have been called "pleiotropic". The cholesterol-independent or "pleiotropic" effects of statins involve improvement of endothelial function, stability of atherosclerotic plaques, decrease of oxidative stress and inflammation, and inhibition of thrombogenic response. These pleiotropic effects of statins have been proposed as key properties of these drugs to reduce cardiovascular morbidity and mortality. The present review will emphasize the molecular mechanisms underlying the effects of statins on endothelial function and oxidative stress. In particular, inhibition of small GTP-binding proteins, Rho, Ras and Rac, which are regulated by isoprenoids [farnesyl pyrophosphate and geranylgeranyl pyrophosphate], seems to play an important role in mediating the pleiotropic effects of statins.
Journal of Pharmacology and Experimental Therapeutics, 2002
LOX-1, a receptor for oxidized low-density lipoprotein (ox-LDL), plays a critical role in endothelial dysfunction and atherosclerosis. LOX-1 activation also plays an important role in monocyte adhesion to endothelial cells. A number of studies show that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) reduce total LDL cholesterol and exert a cardioprotective effect. We examined the modulation of LOX-1 expression and its function by two different statins, simvastatin and atorvastatin, in human coronary artery endothelial cells (HCAECs). We observed that ox-LDL (40 g/ml) treatment upregulated the expression of E-and P-selectins, VCAM-1 and ICAM-1 in HCAECs. Ox-LDL mediated these effects via LOX-1, since antisense to LOX-1 mRNA decreased LOX-1 expression and subsequent adhesion molecule expression. Pretreatment of HCAECs with simvastatin or atorvastatin (1 and 10 M) reduced ox-LDL-induced expression of LOX-1 as well as adhesion molecules (all P Ͻ 0.05). A high concentration of statins (10 M) was more potent than the low concentration (1 M) (P Ͻ 0.05). Both statins reduced ox-LDL-mediated activation of the redox-sensitive nuclear factor-B (NF-B) but not AP-1. These observations indicate that LOX-1 activation plays an important role in ox-LDL-induced expression of adhesion molecules. Inhibition of expression of LOX-1 and adhesion molecules and activation of NF-B may be another mechanism of beneficial effects of statins in vascular diseases.
Statins and Oxidative Stress During Atherogenesis
European Journal of Cardiovascular Prevention & Rehabilitation, 2003
Oxidised low-density lipoprotein (LDL) is believed to be the most atherogenic form of LDL. However, while a number of experimental data support this concept, the protective role of antioxidants that may prevent LDL oxidation in atherosclerosis is only partially confirmed by studies in man. Observational and epidemiological data as well as randomised trials failed to provide clear-cut indications, because of mixed results on the protective role of antioxidants against cardiovascular diseases. In spite of the lack of a general consensus, recent data reinforce the concept that a regular intake of antioxidants present in food blocks the progression of atherosclerosis and that the reduced ability of LDL to oxidise may represent a good marker to follow the action of antioxidants. Among their properties statins also possess antioxidant activities and the aim of this paper is to review the scientific evidence for such an effect and its possible clinical relevance.
Statins in atherosclerosis: lipid-lowering agents with antioxidant capabilities
Atherosclerosis, 2004
Low-density lipoprotein (LDL) cholesterol is an established risk factor for coronary heart disease (CHD). In the presence of oxidative stress LDL particles can become oxidized to form a lipoprotein species that is particularly atherogenic. Indeed, oxidized LDL (oxLDL) is pro-inflammatory, it can cause endothelial dysfunction and it readily accumulates within the arterial wall. Several factors may influence the susceptibility of LDL to oxidation, including its size and composition, and the presence of endogenous antioxidant compounds, such as ␣-tocopherol. Individuals with type 2 diabetes or the metabolic syndrome have high levels of oxidative stress and consequently are at an increased risk for cardiovascular events. Reducing oxidative stress has been proposed as a potential approach to prevent CHD and antioxidant vitamins have been employed with encouraging results in experimental models of atherosclerosis. However, clinical trials have not demonstrated consistent beneficial effects of antioxidants on cardiovascular outcomes. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are the first-line choice for lowering total and LDL cholesterol levels and they have been proven to reduce the risk of CHD. Recent data suggest that these compounds, in addition to their lipid-lowering ability, can also reduce the production of reactive oxygen species and increase the resistance of LDL to oxidation. It may be that the ability of statins to limit the oxidation of LDL contributes to their effectiveness at preventing atherosclerotic disease. (R.S. Rosenson). may also be at increased risk of developing CHD. Indeed, although levels of LDL may not be elevated, its atherogenic potential may be increased by oxidative modification.
European Heart Journal, 2013
Activation of vascular endothelial cells (ECs) contributes importantly to inflammation and atherogenesis. We previously reported that apolipoprotein CIII (apoCIII), found abundantly on circulating triglyceride-rich lipoproteins, enhances adhesion of human monocytes to ECs in vitro. Statins may exert lipid-independent anti-inflammatory effects. The present study examined whether statins suppress apoCIII-induced EC activation in vitro and in vivo. Methods and results Physiologically relevant concentrations of purified human apoCIII enhanced attachment of the monocyte-like cell line THP-1 to human saphenous vein ECs (HSVECs) or human coronary artery ECs (HCAECs) under both static and laminar shear stress conditions. This process mainly depends on vascular cell adhesion molecule-1 (VCAM-1), as a blocking VCAM-1 antibody abolished apoCIII-induced monocyte adhesion. ApoCIII significantly increased VCAM-1 expression in HSVECs and HCAECs. Pre-treatment with statins suppressed apoCIII-induced VCAM-1 expression and monocyte adhesion, with two lipophilic statins (pitavastatin and atorvastatin) exhibiting inhibitory effects at lower concentration than those of hydrophilic pravastatin. Nuclear factor kB (NF-kB) mediated apoCIII-induced VCAM-1 expression, as demonstrated via loss-of-function experiments, and pitavastatin treatment suppressed NF-kB activation. Furthermore, in the aorta of hypercholesterolaemic Ldlr 2/2 mice, pitavastatin administration in vivo suppressed VCAM-1 mRNA and protein, induced by apoCIII bolus injection. Similarly, in a subcutaneous dorsal air pouch mouse model of leucocyte recruitment, apoCIII injection induced F4/80+ monocyte and macrophage accumulation, whereas pitavastatin administration reduced this effect. Conclusions These findings further establish the direct role of apoCIII in atherogenesis and suggest that anti-inflammatory effects of statins could improve vascular disease in the population with elevated plasma apoCIII.