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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1522.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Cholesterol-Lowering Independent Regression and Stabilization of Atherosclerotic Lesions by Pravastatin and by Antimonocyte Chemoattractant Protein-1 Therapy in Nonhuman Primates

Shiro Kitamoto; Kaku Nakano; Yasuhiko Hirouchi; Yoshiro Kohjimoto; Shunichi Kitajima; Makoto Usui; Shujiro Inoue; Kensuke Egashira

From the Department of Cardiovascular Medicine (S.K., K.N., M.U., S.I., K.E.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Primate LTD (H.Y., Y.K., S.K.), Kumamoto, Japan.

Correspondence to Dr Kensuke Egashira, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail egashira{at}cardiol.med.kyushu-u.ac.jp

Objective— Anti-atherosclerotic effects of statins might be mediated partly by pleiotropic cholesterol-lowering independent mechanisms. We used nonhuman primates and examined whether treatment with pravastatin or antimonocyte chemoattractant protein-1 (MCP-1) therapy can induce regression and stabilization of established atherosclerotic lesions through cholesterol-lowering independent mechanisms.

Methods and Results— Advanced atherosclerosis was induced in the abdominal aorta and the common iliac artery of cynomolgus monkeys by undergoing balloon injury and giving atherogenic diet for 6 months. At 6 months, the diet was changed to normal chow, and the animals were allocated to 4 treatment groups: control vehicle group and other groups treated with pravastatin (1 or 10 mg/kg) or with mutant MCP-1 gene transfection for additional 6 months. Each compound was treated instead of the atherogenic diet, and cholesterol contents in pravastatin-treated groups were adjusted to equalize plasma cholesterol level among groups. Pravastatin reduced neointimal formation in the aorta, but not in the common iliac artery. Pravastatin reduced intimal macrophage area and other markers of plaque destabilization in the common iliac artery. Equivalent inhibitory effects were observed in animals that received mutant MCP-1 gene transfection. No serious side effects were noted by 2 therapeutic modalities.

Conclusion— This study demonstrated cholesterol-lowering independent regression and stabilization of established atherosclerotic lesions by pravastatin and by anti-MCP-1 therapy in nonhuman primates. An anti-inflammatory mechanism may be involved in the beneficial effects of pravastatin.

Treatment with pravastatin reduced plaque size and changed characteristics of plaques to more stable phenotype in cynomolgus monkeys with established atherosclerotic lesion independent of cholesterol lowering. Equivalent inhibitory effects were observed in animals that received anti–MCP-1 therapy. An antiinflammatory mechanism might be involved in the pleiotropic chloesterol-lowering independent antiatherosclerotic effects of pravastatin.

Key Words: atherosclerosis • 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors • nonhuman primates • inflammation • regression

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