Anti-atherosclerotic effect of simvastatin depends on the presence of apolipoprotein E.
Low density lipoprotein receptor deficient (LDLR-KO) and apolipoprotein E deficient (apo E-KO) mice both develop hyperlipidemia and atherosclerosis by different mechanisms. The aim of the present study was to compare the effects of simvastatin on cholesterol levels, endothelial dysfunction, and aortic lesions in these two models of experimental atherosclerosis. Male LDLR-KO mice fed a high cholesterol (HC; 1%) diet developed atherosclerosis at 8 months of age with hypercholesterolemia. The addition of simvastatin (300 mg/kg daily) to the HC diet for 2 more months lowered total cholesterol levels by approximately 57% and reduced aortic plaque area by approximately 15% compared with the LDLR-KO mice continued on HC diet alone, P<0.05. Simvastatin treatment also improved acetylcholine (ACh)-induced endothelium-dependent vasorelaxation in isolated aortic rings, which was associated with an increase in NOS-3 expression by approximately 88% in the aorta measured by real time polymerase chain reaction (PCR), P<0.05. In contrast, in age-matched male apo E-KO mice fed a normal diet, the same treatment of simvastatin elevated serum total cholesterol by approximately 35%, increased aortic plaque area by approximately 15%, and had no effect on endothelial function. These results suggest that the therapeutic effects of simvastatin may depend on the presence of a functional apolipoprotein E.
Wang
Yi Xin
YX
Department of Pharmacology, Berlex Biosciences, P.O. Box 4099, 15049 San Pablo Avenue 15049 San Pablo Avenue, Richmond, CA 94804-0099, USA. jim_wang@berlex.com
Martin-McNulty
Baby
B
Huw
Ling Yuh
LY
da Cunha
Valdeci
V
Post
Joe
J
Hinchman
Josephine
J
Vergona
Ronald
R
Sullivan
Mark E
ME
Dole
William
W
Kauser
Katalin
K
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000187:drug effects*; D001161:Arteriosclerosis / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D008076:Cholesterol, HDL / Q000097:blood / Q000187:drug effects; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009126:Muscle Relaxation / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D011973:Receptors, LDL / Q000172:deficiency / Q000187:drug effects; D019821:Simvastatin / Q000627:therapeutic use*; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood; D014665:Vasodilator Agents / Q000494:pharmacology
D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D011973:Receptors, LDL; D014280:Triglycerides; D014665:Vasodilator Agents; D009569:Nitric Oxide; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D000109:Acetylcholine