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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1390.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Farnesyltransferase Inhibitor, Manumycin A, Prevents Atherosclerosis Development and Reduces Oxidative Stress in Apolipoprotein E-Deficient Mice

Michiko Sugita; Hiroki Sugita; Masao Kaneki

From the Department of Anesthesia & Critical Care, Massachusetts General Hospital, Shriners Hospital for Children, Harvard Medical School, Charlestown, Mass.

Correspondence to Dr Masao Kaneki, Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, 149 Thirteenth Street, Rm. 6604, Charlestown, MA 02129. E-mail mkaneki{at}partners.org

Objective— Statins are presumed to exert their antiatherogenic effects in part via lipid-lowering–independent mechanisms. Inhibition of protein farnesylation and/or geranylgeranylation by statins has been postulated to contribute to the lipid-lowering–independent effects. However, a role for protein farnesylation in atherogenesis has not yet been studied. Therefore, we examined the effects of farnesyltransferase inhibitor, manumycin A, on the development of atherosclerosis in apolipoprotein E (apoE)-deficient mice fed a high-fat diet.

Methods and Results— Manumycin A treatment for 22 weeks decreased Ras activity, and reduced fatty streak lesion size at the aortic sinus to 43% of that in vehicle-treated apoE-deficient mice (P<0.05), while plasma total cholesterol was unaltered. Moreover, manumycin A reduced -smooth muscle actin-positive area to 29% of that in vehicle-treated apoE-deficient mice (P<0.01). The prevention of atherogenesis by manumycin A was accompanied by amelioration of oxidative stress, as judged by reduced ex vivo superoxide production and nitrotyrosine immunoreactivity.

Conclusions— These results indicate that the inhibition of farnesyltransferase prevents the development of mature atherosclerosis with concomitant alleviation of oxidative stress in apoE-deficient mice. The present data highlight farnesyltransferase as a potential molecular target for preventive and/or therapeutic intervention against atherosclerosis.

Farnesyltransferase inhibitor, manumycin A, prevented the development of atherosclerosis with concomitant decreases in oxidative stress and Ras activation, with unaltered plasma cholesterol level. These results highlight farnesyltransferase as a molecular target to prevent atherogenesis and suggest that inhibition of farnesylation may be involved in lipid-lowering–independent beneficial effects of statins.

Key Words: apoE-deficient mice • atherosclerosis • farnesyltransferase • oxidative stress • Ras

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