Pravastatin inhibits expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in watanabe heritable hyperlipidemic rabbits - A new pleiotropic effect of statins

Background - LOX-1, a receptor for oxidized low-density lipoprotein ( OxLDL), seems to play a critical role in foam cell formation of macrophages ( M phi s) and smooth muscle cells ( SMC). Inhibition of LOX-1 expression reduces foam cell formation and might influence lipid core formation in atherosclerotic lesions. Because statins are able to downregulate LOX-1 expression in vitro, we examined if pravastatin can be used to reduce LOX-1 expression and lipid core formation in lesions of Watanabe heritable hyperlipidemic ( WHHL) rabbits. Methods and Results - Pravastatin downregulated LOX-1 expression in cultured human M phi s and in cultured human aortic SMCs. Homozygous WHHL rabbits were treated with 50 mg kg(-1) d(-1) pravastatin for 32 weeks. Immunohistochemical studies revealed that LOX-1 was expressed in intimal M phi s and SMCs of atherosclerotic lesions. The pravastatin-treated rabbits showed, compared with untreated rabbits, a significantly reduced LOX-1 protein and mRNA expression in the aortic arch. Lipid labeling of this aorta region also demonstrated a strong reduction of the ratio of lipid core area/total lesion area in pravastatin-treated rabbits. Conclusions - The in vivo inhibition of LOX-1 expression by pravastatin demonstrated here represents a new pleiotropic effect of pravastatin. This in vivo inhibition of LOX-1 might be one mechanism for the lipid core reducing effect of pravastatin in atherogenesis.