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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:604.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Oliver Hofnagel; Birgit Luechtenborg; Heike Eschert; Gabriele Weissen-Plenz; Nicholas J. Severs; Horst Robenek

From Leibniz-Institute for Arteriosclerosis Research at the University Hospital of Muenster (O.H., B.L., G.W.P., H.R.); the Department of Cardiology and Angiology (G.W.P.), Hospital of the University of Muenster, Germany; the Department of Thoracic and Cardiovascular Surgery (H.E., G.W.P.), Hospital of the University of Muenster, Germany; and Imperial College London (N.J.S.), National Heart and Lung Institute, London, UK.

Correspondence to Oliver Hofnagel, Leibniz-Institute for Arteriosclerosis Research, Department of Cell Biology and Ultrastructure Research, Muenster, 48149 Germany. E-mail hofnagel{at}uni-muenster.de

Background— LOX-1, a receptor for oxidized low-density lipoprotein (OxLDL), seems to play a critical role in foam cell formation of macrophages (Ms) 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 Ms 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 Ms 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.

The scavenger receptor LOX-1 seems to play a critical role in foam cell formation of macrophages and smooth muscle cells. Our study demonstrated in vivo inhibition of LOX-1 expression by pravastatin. This new pleiotropic effect of pravastatin might be one mechanism for the lipid core reducing effect of pravastatin in atherogenesis.

Key Words: atherosclerosis • cardiovascular disease prevention • lipoproteins • oxidized lipids • smooth muscle cells

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