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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:917.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Eplerenone With Valsartan Effectively Reduces Atherosclerotic Lesion by Attenuation of Oxidative Stress and Inflammation

Jun Suzuki; Masaru Iwai; Masaki Mogi; Akira Oshita; Toyofumi Yoshii; Jitsuo Higaki; Masatsugu Horiuchi

From the Department of Molecular and Cellular Biology (J.S., M.I., M.M., A.O., T.Y., M.H.), Division of Medical Biochemistry and Cardiovascular Biology, and Second Department of Internal Medicine (J.S., A.O., T.Y., J.H.), Ehime University School of Medicine, Japan. J.S.’s current address: Cardiovascular Research Institute, University of Rochester, 601 Elmwood Ave, Box 679/CVRI, Rochester, NY 14642.

Correspondence to Masatsugu Horiuchi, MD, PhD, FAHA, Department of Molecular and Cellular Biology, Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp

Objective— Angiotensin II contributes to atherogenesis, mainly through oxidative stress and inflammation. Recent data suggest that aldosterone is implicated in some effects of angiotensin II. We hypothesized that aldosterone could directly contribute to oxidative stress and atherosclerotic lesion formation.

Methods and Results— Male apolipoprotein E–deficient mice 6 weeks of age were placed on a normal diet or 1.25% high-cholesterol diet. After 6 weeks of the high-cholesterol diet, a marked increase in atherosclerotic lesion formation was observed in the aorta, accompanied by significant elevation of plasma cholesterol level. Production of superoxide anion and expression of NAD(P)H oxidase subunit p47^phox, tumor necrosis factor-, and monocyte chemoattractant protein-1 in the aorta were increased with the high-cholesterol diet. Eplerenone (1.67 g/kg in high-cholesterol diet) did not affect blood pressure or plasma cholesterol but decreased the atherosclerotic area by nearly 70% (P<0.05), associated with attenuation of oxidative stress and inflammatory response. Valsartan (0.5 mg/kg per day) also decreased the atherosclerotic lesion, whereas coadministration of valsartan and eplerenone further decreased it. Moreover, aldosterone (0.1 µmol/L) enhanced NADPH oxidase activity in cultured vascular smooth muscle cells.

Conclusions— These results suggest that aldosterone may play a critical role in atherogenesis subsequent to oxidative stress in part independent of angiotensin II–mediated signaling, and that eplerenone could prevent atherosclerosis by attenuating oxidative stress and inflammation.

Eplerenone (1.67 g/kg in 1.25% high-cholesterol diet) inhibited the increase in atherosclerotic lesion formation, oxidative stress, and inflammation in male apolipoprotein E–deficient mice treated with a high-cholesterol diet. Eplerenone also enhanced the inhibitory action of an AT₁ receptor blocker, valsartan, suggesting the beneficial effect of combination therapy for atherosclerosis.

Key Words: angiotensin • aldosterone • receptors • oxidative stress • atherosclerosis

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