Ah. Wagner et al., Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation, ART THROM V, 20(1), 2000, pp. 61-69
Three 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors
(HCRIs), atorvastatin, pravastatin, and cerivastatin, inhibited phorbol est
er-stimulated superoxide anion (O-2(-)) formation in endothelium-intact seg
ments of the rat aorta in a time- and concentration-dependent manner (maxim
um inhibition of 70% after 18 hours at 1 to 10 mu mol/L). The HMG-CoA reduc
tase product mevalonic acid (400 mu mol/L) reversed the inhibitory effect o
f the HCRIs, which, conversely, was mimicked by inactivation of p21 Rac wit
h Clostridium sordellii lethal toxin but not by inactivation of p21 Rho wit
h Clostridium botulinum exoenzyme (C3). A mevalonate sensitive inhibition o
f phorbol ester-stimulated O-2(-) formation by atorvastatin was also observ
ed in porcine cultured endothelial cells and in a murine macrophage cell li
ne. In the rat aorta, no effect of the HCRIs on protein kinase C, NADPH oxi
dase, or superoxide dismutase (SOD) activity and expression was detected, w
hereas that of endothelial nitric oxide (NO) synthase was enhanced approxim
ate to 2-fold. Moreover, exposure of the segments to atorvastatin resulted
in a significant improvement of endothelium-dependent NO-mediated relaxatio
n, and this effect was abolished in the presence of SOD. Taken together, th
ese findings suggest that in addition to augmenting endothelial NO synthesi
s, HCRIs inhibit endothelial O-2(-) formation by preventing the isoprenylat
ion of p21 Rac, which is critical for the assembly of NADPH oxidase after a
ctivation of protein kinase C. The resulting shift in the balance between N
O and O-2(-) in the endothelium improves endothelial function even in healt
hy blood vessels and therefore may provide a reasonable explanation for the
beneficial effects of HCRIs in patients with coronary heart disease in add
ition to or as an alternative to the reduction in serum LDL cholesterol.