A HMG-CoA reductase inhibitor possesses a potent anti-atherosclerotic effect other than serum lipid lowering effects - the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action

We have determined whether the anti-atherosclerotic effect of a 3-hydroxy-3 -methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (fluvastatin) is mediate d through nitric oxide (NO) as well as affecting plasma lipids. NO related vascular responses, endothelial nitric oxide synthase (eNOS) mRNA and super oxide anion (O-2(-)) release were examined in vascular walls of oophorectom ized female rabbits fed 0.5%, cholesterol chow for 12 weeks with or without fluvastatin (2 mg/kg per day). Serum lipid profile was not different betwe en two groups. NO dependent responses stimulated by acetylcholine and calci um ionophore A23187 and tone related basal NO response induced by N-G-monom ethyl-L-arginine acetate (L-NMA): nitric oxide synthase inhibitor were all improved by fluvastatin treatment. Endothelium independent vasorelaxation i nduced by nitroglycerin was not different between the two groups of rabbits ' arteries. Fluvastatin treatment increased cyclic GMP concentration in aor ta of rabbits, eNOS mRNA expression and O-2(-) release were measured in aor ta using competitive reverse transcription-polymerase chain reaction (RT-PC R) and with lucigenin analogue, 2-methyl-3,7-dihydroimidazol [1.2-a]pyrazin e-3-one (MCLA) chemiluminescence methods. eNOS mRNA in the endothelial cell s of aorta was significantly up-regulated and O-2(-) production was signifi cantly reduced in fluvastatin treated rabbit aorta. Anti-macrophage stainin g area, but not anti-smooth muscle cell derived actin stained area in the a orta was also reduced by fluvastatin treatment. Conclusion, fluvastatin, a HMG-CoA reductase inhibitor, retards the initiation of atherosclerosis form ation through the improvement of NO bioavailability by both up-regulation o f eNOS mRNA acid decrease of O-2(-) production in vascular endothelial cell s, and this means that part of the anti-atherosclerotic effect of fluvastat in may be due to nonlipid factors. (C) 2001 Elsevier Science Ireland Ltd. A ll rights reserved.