Statins Control Oxidized LDL-Mediated Histone Modifications and Gene Expression in Cultured Human Endothelial Cells (original) (raw)
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Journal of the American Heart Association, 2016
Activated T cells and dendritic cells (DCs) are colocalized in atherosclerotic plaques in association with plaque rupture. Oxidized low-density lipoprotein (oxLDL) promotes immune activation and inflammation. We studied the effects of statins (atorvastatin and simvastatin) on human DC maturation and T-cell activation. Human peripheral blood monocytes were differentiated to DCs and stimulated with oxLDL. T cells were isolated from carotid endarterectomy specimens from patients undergoing carotid endarterectomy or from healthy individuals. Naïve T cells were cocultured with pretreated DCs. The effects of statin were studied. OxLDL induced DC maturation and T-cell activation. OxLDL induced atherogenic heat shock proteins (HSP) 60 and 90 and decreased potentially atheroprotective heat shock protein 27, effects restored by atorvastatin. T cells exposed to oxLDL-treated DCs produced interferon-γ and interleukin (IL)-17. Atorvastatin and simvastatin suppressed the DC maturation showing low...
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 as Pleiotropic Modifiers of Vascular Oxidative Stress and Inflammation
The Journal of Critical Care Medicine, 2015
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the industrialized world and in the future is expected to be the number one killer worldwide. The main cause underlying CVD is atherosclerosis. A key event in atherosclerosis initiation and progression is oxidative stress through the production of reactive oxygen species as well as endothelial dysfunction. Several pro- inflammatory and anti-inflammatory cytokines and proteins are involved in this process, complemented by activation of adhesion molecules that promote leukocyte rolling, tethering and infiltration into the sub-endothelial space. Statins represent the agent of choice since numerous clinical trials have verified that their pharmacological action extends beyond lipid lowering. Statins demonstrate direct anti-oxidant effects by scavenging free radicals and stimulating anti-oxidant enzymes while acting as regulators for cytokine, protein and adhesion molecule expression, all of which are involve...
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.
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.
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.
American Journal of Physiology-Renal Physiology, 2007
LDL receptor (LDLr) is widely expressed in both liver and peripheral tissue. We aimed to clarify tissue-specific regulation of LDLr in hepatic cell line (HepG2) cells and human kidney mesangial cells (HMCs) under physiological and inflammatory conditions. We have demonstrated that the concentration of LDL required for 50% inhibition of LDLr mRNA expression (IC50) in HepG2 was 75 μg/ml, but only 30 μg/ml in HMCs. The concentration of mevastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, which achieved 200% upregulation of LDLr (UC200) in HepG2 cells, was 0.7 μM, which is much lower than 2.8 μM in HMCs. Inflammatory stress increased IC50to 80 and 75 μg/ml of LDL, UC200to 2.8 μM, and 4.2 μM of mevastatin in HepG2 and HMCs. There was obvious sterol-regulatory element binding protein cleavage-activating protein accumulation in the Golgi in HepG2 cells, but not in HMCs in the presence of high concentration of LDL. IL-1β further increased sterol-regulatory element bindin...
Molecular Mechanisms of HDL-Cholesterol Elevation by Statins and Its Effects on HDL Functions
Journal of Atherosclerosis and Thrombosis, 2010
Numerous large-scale clinical studies have revealed that the low-density lipoprotein cholesterol (LDL-C)-lowering effect of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) prevents coronary heart disease (CHD). Statins have not only LDL-C-lowering effects but also high-density lipoprotein cholesterol (HDL-C)-elevating effects, which differ among statins. In this article, we discuss the molecular mechanisms of HDL-C elevation by statins and its effect on HDL functions. We summarize the reports to date on the effects of statins on various proteins, enzymes and receptors involved in reverse cholesterol transport (RCT), which is one of the protective systems against atherosclerosis. Since statins increase the synthesis of apolipoprotein A-I (ApoA-I) and HDL neogenesis in the liver, the HDL-C-increasing effect of statins may reflect RCT activation. Moreover, HDL has pleiotropic effects, including anti-inflammatory and anti-oxidative effects, as well as RCT. In the future, it may be necessary to assess the functions of HDL elevated by statins, and select statins based on differences in their effects in clinical practice.
Clinical Science, 2004
ICAM-1 (intercellular cell-adhesion molecule-1) and VCAM-1 (vascular cell-adhesion molecule-1) are cell-adhesion molecules that have an essential role in monocyte recruitment. In the present study we have investigated (i) whether statins reduce soluble levels of ICAM-1 (sICAM-1) and VCAM-1 (sVCAM-1), and the relationship between resistance of LDL (low-density lipoprotein) to in vitro oxidation and sICAM-1 and sVCAM-1 levels. Whole blood samples were obtained from 55 healthy non-smoking adults (aged 35-65 years) with moderate (LDL-cholesterol, 3.4-4.9 mmol/l) hypercholesterolaemia participating in a randomized double-blinded, 8-week trial comparing pravastatin (40 mg), simvastatin (20 and 80 mg) and placebo. sICAM-1 levels (means + − S.D.) increased slightly from 12.2 + − 4.2 to 13.6 + − 4.2 ng/ml with statin therapy, whereas, among placeboassigned subjects, levels were unchanged (11.8 + − 5.0 and 11.8 + − 3.9 ng/ml). sVCAM-1 increased from 18.9 + − 10.1 to 21.1 + − 7.4 ng/ml among those on active therapy and slightly declined with placebo assignment (19.8 + − 8.8 to 19.4 + − 6.4 ng/ml). Lag times increased with statin therapy from 74.3 + − 39.8 min to 98.3 + − 57.8 min (P = 0.003), and were unchanged in the placebo group (from 103.1 + − 61.1 to 90.8 + − 65.9 min; P = 0.48). There were no significant changes between statin and placebo therapy for sICAM-1, sVCAM-1 or lag times (P = 0.09, 0.16 and 0.067 respectively). Changes in sICAM-1 and sVCAM-1 were not correlated with the change in lag times. In contrast with the known effects of oxidized LDL on gene activation of ICAM-1 and VCAM-1, lag times did not correlate with sICAM-1 and sVCAM-1. Statin therapy improved lag times, but has no effect on sICAM-1 or sVCAM-1 levels.