on January 22, 2008
Published online before print January 22, 2008, doi: 10.1161/CIRCULATIONAHA.107.712539
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Submitted on May 1, 2007
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. * To whom correspondence should be addressed. E-mail: watanabemd{at}med.showa-u.ac.jp.
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- 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-
Accepted on November 27, 2007
Impact of Salusin-
Takuya Watanabe MD, PhD*, 
and -
on Human Macrophage Foam Cell Formation and Coronary Atherosclerosis
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 -
were detected in human coronary atherosclerotic plaques, with dominance of salusin- 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-. Salusin- significantly reduced ACAT-1 expression in a concentration-dependent manner. In contrast, salusin- 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-; however, neither salusin- nor salusin- 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. and suppressed by salusin- via ACAT-1 regulation.
Key words: atherosclerosis • coronary disease • peptides • plaque • salusin-
, human •
salusin-, human
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