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(Circulation. 2008;117:638-648.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Impact of Salusin- and -β on Human Macrophage Foam Cell Formation and Coronary Atherosclerosis

Takuya Watanabe, MD, PhD; Kae Nishio, MS; Tomoko Kanome, MS; Taka-aki Matsuyama, MD, PhD; Shinji Koba, MD, PhD; Tetsuo Sakai, MD, PhD; Kengo Sato, MS; Shigeki Hongo, PhD; Kiyoshi Nose, PhD; Hidekazu Ota, MD, PhD; Youichi Kobayashi, MD, PhD; Takashi Katagiri, MD, PhD; Masayoshi Shichiri, MD, PhD; Akira Miyazaki, MD, PhD

From the Department of Biochemistry (T.W., K. Nishio, T. Kanome, S.H., A.M.), Second Department of Pathology (T.M., H.O.), and Third Department of Internal Medicine (S.K., T.S., Y.K., T. Katagiri), Showa University School of Medicine, Tokyo, Japan; Department of Microbiology, Showa University School of Pharmaceutical Sciences (K. Nose), Tokyo, Japan; and Tokyo Medical and Dental University (K.S., M.S.), Tokyo, Japan.

Correspondence to Takuya Watanabe, MD, PhD, Department of Biochemistry, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. E-mail watanabemd{at}med.showa-u.ac.jp

Received May 1, 2007; accepted November 27, 2007.

Background— Human salusins, related bioactive polypeptides with mitogenic effects on vascular smooth muscle cells and fibroblasts and roles in hemodynamic homeostasis, may be involved in the origin of coronary atherosclerosis. Macrophage foam cell formation, characterized by cholesterol ester accumulation, is modulated by scavenger receptor (cholesterol influx), acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1; storage cholesterol ester converted from free cholesterol), and ATP-binding cassette transporter A1 (cholesterol efflux).

Methods and Results— Serum salusin- levels were decreased in 173 patients with angiographically proven coronary artery disease compared with 40 patients with mild hypertension and 55 healthy volunteers (4.9±0.6 versus 15.4±1.1 and 20.7±1.5 pmol/L, respectively; P<0.0001). Immunoreactive salusin- and -β were detected in human coronary atherosclerotic plaques, with dominance of salusin-β in vascular smooth muscle cells and fibroblasts. After 7 days in primary culture, acetylated low-density lipoprotein–induced cholesterol ester accumulation in human monocyte-derived macrophages was significantly decreased by salusin- and increased by salusin-β. Salusin- significantly reduced ACAT-1 expression in a concentration-dependent manner. In contrast, salusin-β significantly increased ACAT-1 expression by 2.1-fold, with a maximal effect at 0.6 nmol/L. These effects of salusins were abolished by G-protein, c-Src tyrosine kinase, protein kinase C, and mitogen-activated protein kinase kinase inhibitors. ACAT activity and ACAT-1 mRNA levels were also significantly decreased by salusin- and increased by salusin-β; however, neither salusin- nor salusin-β affected scavenger receptor A function assessed by [¹²⁵I]acetylated low-density lipoprotein endocytosis or scavenger receptor class A and ATP-binding cassette transporter A1 expression.

Conclusions— Our results indicate that the 2 salusin isoforms have opposite effects on foam cell formation in human monocyte-derived macrophages. Development of atherosclerosis may be accelerated by salusin-β and suppressed by salusin- via ACAT-1 regulation.

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CLINICAL PERSPECTIVE

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