Fluvastatin suppresses atherosclerotic progression, mediated through its inhibitory effect on endothelial dysfunction, lipid peroxidation, and macrophage deposition.
Fluvastatin, a potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, exerts an inhibitory effect on intimal thickening after mechanical injury in normocholesterolemic rabbit artery at a dose not enough to elicit a known action of lipid lowering. This study was designed to determine whether atherosclerotic progression triggered by hypercholesterolemia can be inhibited by fluvastatin under conditions without its hypocholesterolemic effect. Rabbits were fed a 0.5% cholesterol diet or normal diet for 17 weeks and were treated with either fluvastatin (0.3-2 mg/kg/day, p.o.) or pravastatin (2 mg/kg/day, p.o.). Atherogenic features manifested in the cholesterol-diet group, compared with the normal-diet group; they were the increase in serum lipid peroxide level, in the intraluminal lesion area of the aorta, and in macrophage content of the aortic cross-sectional lesion area; the attenuation of endothelium-dependent relaxing response to acetylcholine in the femoral artery; and the increase in serum lipid level. Treatment with fluvastatin, but not pravastatin, inhibited the manifestation of the atherogenic features without a serum lipid-lowering effect. Thus fluvastatin is likely to reduce the risk of atherosclerotic progression, to which endothelial dysfunction, lipid peroxidation, and macrophage accumulation in the vasculature may contribute, irrespective of changes in serum lipid levels.
Bandoh
T
T
Department of Pharmacology, Sandoz Tsukuba Research Institute, Tsukuba, Japan. tsutomu.bando@pharma.novartis.com
Mitani
H
H
Niihashi
M
M
Kusumi
Y
Y
Kimura
M
M
Ishikawa
J
J
Totsuka
T
T
Sakurai
I
I
Hayashi
S
S
D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000473:pathology; D002791:Cholesterol, Dietary / Q000009:adverse effects; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use*; D000077340:Fluvastatin; D006462:Hemolytic Plaque Technique; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008054:Lipid Peroxides / Q000097:blood; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D017035:Pravastatin / Q000627:therapeutic use; D011817:Rabbits; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000924:Anticholesteremic Agents; D002791:Cholesterol, Dietary; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008054:Lipid Peroxides; D008055:Lipids; D017392:Thiobarbituric Acid Reactive Substances; D000077340:Fluvastatin; D017035:Pravastatin