Improvement of Nitric Oxide–Dependent Vasodilatation by HMG-CoA Reductase Inhibitors Through Attenuation of Endothelial Superoxide Anion Formation

Abstract

Abstract-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. Key Words: HMG-CoA reductase inhibitor(s) Ⅲ endothelial dysfunction Ⅲ coronary heart disease Ⅲ nitric oxide Ⅲ superoxide anion Ⅲ NADPH oxidase Ⅲ p21 Rac T he beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (HCRIs), collectively referred to as "statins," on coronary events have generally been attributed to the well-documented LDL cholesterol-lowering properties of these drugs. However, despite the strong association between drug concentration, blood lipid level, and patient benefit shown in the CARE, 4S, and WOSCOPS trials, HCRIs seem to exert at least part of their cardioprotective action by mechanisms other than simply lowering the lipid load of the vessel wall. Thus, HCRIs induce regression of atherosclerotic lesions in patients with coronary heart disease (CHD) with and without hypercholesterolemia 1 and improve endothelial dysfunction, a hallmark of atherosclerotic blood vessels, in patients with moderately elevated total serum cholesterol within 1 month. 2 At the cellular level, they modulate leukocyte activity and adhesiveness, 3,4 inhibit vascular smooth muscle cell proliferation both in vitro and in vivo, 5,6 and reduce the synthesis of che...

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

“…In addition to effects on NO production, statins inhibit formation of oxygen radicals by ECs (77,78). Two mechanisms appear responsible for this observed effect.…”

“…Two mechanisms appear responsible for this observed effect. First, statins prevent activation of the NADPH oxidase complex, which generates superoxide, apparently due to their inhibitory effect on the Rho family GTPase Rac-1 (77,79). Second, statins inhibit angiotensin-induced NADPH oxidase activation by down-regulating the concentration of the angiotensin II type 1 receptor (79).…”

Statins as Regulators of Redox State in the Vascular Endothelium: Beyond Lipid Lowering

“…The effects of statins on NADPH oxidase have also been examined in animal models that exhibit various CVD states. Statin administration in rats has been shown to suppress NADPH oxidase activity through a mevalonate-dependent prevention of Rac activation, leading to improved vascular NO availability and subsequently improved endothelial function (113). In atherosclerotic rabbits, fluvastatin treatment prevents an increase in p22 phox and gp91 phox induced by highfat diet, improving endothelial function and reducing plaque size (68).…”

Estatinas: efeitos pleiotrópicos. Statins: pleiotropic effects

“…Entre eles: I) a diminuição da hipercolesterolemia inibe a produção de radicais livres de oxigênio, que consomem óxido nítrico e reduzem sua produção; II) as estatinas podem melhorar a síntese do óxido nítrico pelo estímulo da enzima óxido nítrico-sintetase (CHEN et al, 2000); III) inibição da síntese do mevalonato e formação da proteína Rho que pode diminuir a formação da óxido nítrico-sintetase (LAUFS et al, 2000;WAGNER et al, 2000); IV) decréscimo na produção de ânion superóxido pela NADPH oxidase (WASSMAN et al, 2002).…”