Anti-atherogenic effect of statins: role of nitric oxide, peroxynitrite and haem oxygenase-1 (original) (raw)
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Circulation, 2011
Background-Treatment with statins improves clinical outcome, but the exact mechanisms of pleiotropic statin effects on vascular function in human atherosclerosis remain unclear. We examined the direct effects of atorvastatin on tetrahydrobiopterin-mediated endothelial nitric oxide (NO) synthase coupling in patients with coronary artery disease. Methods and Results-We first examined the association of statin treatment with vascular NO bioavailability and arterial superoxide (O 2 ·Ϫ ) in 492 patients undergoing coronary artery bypass graft surgery. Then, 42 statin-naïve patients undergoing elective coronary artery bypass graft surgery were randomized to atorvastatin 40 mg/d or placebo for 3 days before surgery to examine the impact of atorvastatin on endothelial function and O 2 ·Ϫ generation in internal mammary arteries. Finally, segments of internal mammary arteries from 26 patients were used in ex vivo experiments to evaluate the statin-dependent mechanisms regulating the vascular redox state. Statin treatment was associated with improved vascular NO bioavailability and reduced O 2 ·Ϫ generation in internal mammary arteries. Oral atorvastatin increased vascular tetrahydrobiopterin bioavailability and reduced basal and N-nitro-L-arginine methyl ester-inhibitable O 2 ·Ϫ in internal mammary arteries independently of low-density lipoprotein lowering. In ex vivo experiments, atorvastatin rapidly improved vascular tetrahydrobiopterin bioavailability by upregulating GTP-cyclohydrolase I gene expression and activity, resulting in improved endothelial NO synthase coupling and reduced vascular O 2 ·Ϫ . These effects were reversed by mevalonate, indicating a direct effect of vascular hydroxymethylglutaryl-coenzyme A reductase inhibition.
Prevention of Atherosclerosis by Interference with the Vascular Nitric Oxide System
Bentham Science Publishers
Nitric oxide (NO) produced by endothelial NO synthase (eNOS) represents an anti-atherosclerotic principle. NO bioavailability is decreased in atherosclerosis due to increased NO inactivation by reactive oxygen species and reduced NO synthesis. Various types of vascular pathophysiology are associated with oxidative stress, with NADPH oxidases as the major source of reactive oxygen species. These inactivate NO. Also, oxidative stress is likely to be the main cause for oxidation of the essential NOS cofactor, tetrahydrobiopterin (BH4). A lack of BH4 leads to eNOS uncoupling (i.e., uncoupling of oxygen reduction from NO synthesis in eNOS). Based on these pathomechanisms, the therapeutic potential of a number of compounds is discussed in this review: (1) NO donors; (2) L-arginine; (3) folic acid; (4) BH4 and its precursor sepiapterin; (5) compounds that upregulate eNOS and concomitantly maintain eNOS activity (e.g. midostaurin, betulinic acid, ursolic acid, AVE9488 and AVE3085); (6) compounds that enhance the de novo synthesis of BH4 by stimulating expression or activity of GTP cyclohydrolase I; and (7) 3-hydroxy-3-methylglutarylcoenzyme A inhibitors (statins) and drugs interrupting the renin-angiotensin-aldosterone system. Statins, angiotensin II type 1 receptor blockers, angiotensin-converting enzyme (ACE) inhibitors, the aldosterone antagonist eplerenone and the renin inhibitor aliskiren enhance NO bioactivity and reduce atherosclerosis progression through multiple mechanisms.
Atherosclerosis, 2006
Beneficial cardiovascular effects of statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are particularly assigned to the modulation of inflammation. Endothelial nitric oxide synthase (eNOS) and heme oxygenase-1 (HO-1) are listed among the crucial protective, anti-inflammatory genes in the vasculature. Here we show that atorvastatin at pharmacologically relevant concentration (0.1 M) enhanced the expression of eNOS in human microvascular endothelial cells (HMEC-1). Moreover, atorvastatin prevented hypoxiainduced decrease in eNOS expression. However, in the same cells atorvastatin was ineffective in modulation of HO-1 protein level. Therefore, we suggest that the protective effect of statins at their pharmacological concentrations is not mediated by enhancement of HO-1 activity, but may involve eNOS.
British Journal of Pharmacology, 2002
Animal experimental studies have demonstrated that inducible nitric oxide synthase (iNOS) expression correlates with neointima formation and is prevented by HMG-CoA reductase inhibitors (statins). In the present study we have investigated the underlying mechanism of action of these drugs in isolated segments of the rat aorta. 2 Western blot analysis and immunohistochemistry revealed that tumour necrosis factor a (TNFa) plus interferon-g (IFNg) synergistically induce iNOS gene expression in the endothelium but not in the smooth muscle of these segments while constitutive endothelial NO synthase (eNOS) abundance was markedly reduced. 3 Pre-treatment with 1 ± 10 mM atorvastatin, cerivastatin or pravastatin decreased TNFa plus IFNg stimulated iNOS expression in the endothelium irrespective of the presence of the HMG-CoA reductase product mevalonate (400 mM). 4 Electrophoretic mobility shift assay experiments con®rmed that the combination of TNFa plus IFNg causes activation of the transcription factors STAT-1 and NF-kB in native endothelial cells. Neutralization of these transcription factors by employing the corresponding decoy oligonucleotides con®rmed their involvement in TNFa plus IFNg stimulated iNOS expression. Translocation of both transcription factors was attenuated by atorvastatin, and this eect was insensitive to exogenous mevalonate. 5 The present ®ndings thus demonstrate a speci®c HMG-CoA reductase-independent inhibitory eect of statins, namely atorvastatin, on cytokine-stimulated transcription factor activation in native endothelial cells in situ and the subsequent expression of a gene product implicated in vascular in¯ammation. This eect may be therapeutically relevant and in addition provide an explanation for the reported rapid onset of action of these drugs in humans.
Atherosclerosis, 1999
HMG-CoA reductase inhibitors have been shown to be effective in primary and secondary prevention of coronary heart disease. Their mechanism of action is attributed to their cholesterol lowering activity but recent results seem to indicate additional effects related to the modulation of other processes that regulate the presentation of vascular diseases. Our objective has been to study the effects of atorvastatin and simvastatin, two HMG-CoA reductase inhibitors, on lesion composition and expression of genes involved in lesion development in a diet-induced atherosclerotic rabbit model. Both HMG-CoA reductase inhibitors were administered at identical doses of 2.5 mg/kg per day with the hyperlipemic diet for 10 weeks. Both statins significantly prevented the diet-induced increase in cholesterol levels. Relative lesion composition in fibrinogen, macrophages and smooth muscle cells was unaltered by the treatment although lesion size was reduced; therefore, both HMG-CoA reductase inhibitors reduced total amounts of fibrinogen, macrophages and smooth muscle cells (simvastatin, P B0.05). NOS II gene expression was positively and significantly correlated with lesion size and inversely correlated with HDL plasma levels. NOS II expression was markedly downregulated in simvastatin treated animals while MCP-1 was unaltered. Therefore, HMG-CoA reductase inhibition seems to interfere with atherosclerotic lesion development by reducing intimal thickening development and the expression of the cytotoxic NOS II.
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2007
Endothelial dysfunction and atherosclerosis are associated with an inflammation-induced decrease in endothelial nitric oxide synthase (eNOS) expression. Based on the differences between hydrophobic and hydrophilic statins in their reduction of cardiac events, we analyzed the effects of rosuvastatin and cerivastatin on eNOS and inducible NO synthase (iNOS) expression and NOS activity in TNF-alpha-stimulated human umbilical vein endothelial cells (HUVEC). Both statins reversed down-regulation of eNOS mRNA and protein expression by inhibiting HMG-CoA reductase and isoprenoid synthesis. Cerivastatin tended to a more pronounced effect on eNOS expression compared to rosuvastatin. NOS activity - measured by conversion of [(3)H]-L-arginine to [(3)H]-L-citrulline - was enhanced under treatment with both drugs due to inhibition of HMG-CoA reductase. Statin-treatment reduced iNOS mRNA expression under normal conditions, but had no relevant effects on iNOS mRNA expression in cytokine-treated ce...
Arteriosclerosis, Thrombosis, and Vascular Biology, 2000
Three 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (HCRIs), atorvastatin, pravastatin, and cerivastatin, inhibited phorbol ester-stimulated superoxide anion (O 2 Ϫ) formation in endothelium-intact segments of the rat aorta in a time-and concentration-dependent manner (maximum inhibition of 70% after 18 hours at 1 to 10 mol/L). The HMG-CoA reductase product mevalonic acid (400 mol/L) reversed the inhibitory effect of the HCRIs, which, conversely, was mimicked by inactivation of p21 Rac with Clostridium sordellii lethal toxin but not by inactivation of p21 Rho with Clostridium botulinum exoenzyme (C3). A mevalonate-sensitive inhibition of phorbol ester-stimulated O 2 Ϫ formation by atorvastatin was also observed in porcine cultured endothelial cells and in a murine macrophage cell line. In the rat aorta, no effect of the HCRIs on protein kinase C, NADPH oxidase, or superoxide dismutase (SOD) activity and expression was detected, whereas that of endothelial nitric oxide (NO) synthase was enhanced Ϸ2-fold. Moreover, exposure of the segments to atorvastatin resulted in a significant improvement of endothelium-dependent NO-mediated relaxation, and this effect was abolished in the presence of SOD. Taken together, these findings suggest that in addition to augmenting endothelial NO synthesis, HCRIs inhibit endothelial O 2 Ϫ formation by preventing the isoprenylation of p21 Rac, which is critical for the assembly of NADPH oxidase after activation of protein kinase C. The resulting shift in the balance between NO and O 2 Ϫ in the endothelium improves endothelial function even in healthy blood vessels and therefore may provide a reasonable explanation for the beneficial effects of HCRIs in patients with coronary heart disease in addition to or as an alternative to the reduction in serum LDL cholesterol.