title: Antiinflammatory and antiarteriosclerotic actions of HMG-CoA reductase inhibitors in a rat model of chronic inhibition of nitric oxide synthesis.
abstract: Recent studies suggest that some of the beneficial effects of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may be due to their cholesterol-lowering independent effects on the blood vessels. Chronic inhibition of endothelial nitric oxide (NO) synthesis by oral administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) to rats induces early vascular inflammation as well as subsequent arteriosclerosis. The aim of the study is to test whether treatment with statins attenuates such arteriosclerotic changes through their cholesterol-lowering independent effects. We investigated the effect of statins (pravastatin and cerivastatin) on the arteriosclerotic changes in the rat model. We found that treatment with statins did not affect serum lipid levels but markedly inhibited the L-NAME-induced vascular inflammation and arteriosclerosis. Treatment with statins augmented endothelial NO synthase activity in L-NAME-treated rats. We also found the L-NAME induced increase in Rho membrane translocation in hearts and its prevention by statins. Such vasculoprotective effects of statins were suppressed by the higher dose of L-NAME. In summary, in this study, we found that statins such as pravastatin and cerivastatin inhibited vascular inflammation and arteriosclerosis through their lipid-lowering independent actions in this model. Such antiarteriosclerotic effects may involve the increase in endothelial NO synthase activity and the inhibition of Rho activity.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: W
authors.initials: W
authors.lastname: Ni
authors.forename: K
authors.initials: K
authors.lastname: Egashira
authors.forename: C
authors.initials: C
authors.lastname: Kataoka
authors.forename: S
authors.initials: S
authors.lastname: Kitamoto
authors.forename: M
authors.initials: M
authors.lastname: Koyanagi
authors.forename: S
authors.initials: S
authors.lastname: Inoue
authors.forename: A
authors.initials: A
authors.lastname: Takeshita
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics; D003331:Coronary Vessels / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000276:immunology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D019335:Nitroarginine / Q000097:blood; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects / Q000378:metabolism; D017035:Pravastatin / Q000097:blood / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011725:Pyridines / Q000097:blood / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D013599:Systole; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D020742:rhoA GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D018932:Chemokine CCL2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D009566:Nitrates; D009573:Nitrites; D018809:Proliferating Cell Nuclear Antigen; D011725:Pyridines; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019335:Nitroarginine; C086276:cerivastatin; D019001:Nitric Oxide Synthase; D007703:Peptidyl-Dipeptidase A; D020742:rhoA GTP-Binding Protein; D017035:Pravastatin; D019331:NG-Nitroarginine Methyl Ester