HMG-CoA reductase inhibitor, fluvastatin, has cholesterol-lowering independent "direct" effects on atherosclerotic vessels in high cholesterol diet-fed rabbits

Hironobu Mitani, Kensuke Egashira, Masaaki Kimura

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36 Citations (Scopus)

Abstract

Recent clinical studies suggest that some of the beneficial effects of 3-hydroxy-3-metylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on the incidence of myocardial infarctions and ischemic strokes may be through their non-cholesterol-lowering "direct" effects on atherosclerotic vessels. We designed this study to test the hypothesis that fluvastatin inhibits atheroma formation and increase plaque stability independent of cholesterol-lowering effects. Rabbits were fed 0.5% high-cholesterol diet for 12 weeks (progression phase) and then fed the high-cholesterol diet either containing or not containing fluvastatin 2mg/kg per day for additional 8 weeks (treatment phase). Rabbits fed normal diet were used as control. Plasma total and LDL-cholesterol concentrations did not differ during the treatment phase of the experiment. Atherosclerotic changes (plaque formation, lipid- and macrophage-rich intimal thickening, the increase in MCP-1, IL-8, TNF-α, IL-1β, M-CSF, MMP-1, MMP-9, MMP-12, and ACE mRNA expression, and the increase in plasma MCP-1 levels) were observed in the high-cholesterol diet group (HC). All of these changes were less in the fluvastatin-treated group (HC+Flu) than in HC. There was no significant difference in aortic collagen (type I and type IV) mRNA expression between groups. Furthermore, fluvastatin increased the extracellular matrix content (collagen) and vascular smooth muscle cell composition in the atherosclerotic lesion, leading to the increase in plaque stability score (collagen+smooth muscle cell area)/(macrophage+lipid deposition area) in HC+Flu. Fluvastatin not only reduced atherogenesis but also to stabilized vulnerable atheromatous plaques in atherosclerotic rabbits, presumably through the macrophage recruitment and activation in the aortic lesion, at a low dose without cholesterol-lowering effects.

Original languageEnglish
Pages (from-to)417-427
Number of pages11
JournalPharmacological Research
Volume48
Issue number5
DOIs
Publication statusPublished - Nov 1 2003

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All Science Journal Classification (ASJC) codes

  • Pharmacology

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