Impact of Salusin- (cid:1) and - (cid:2) on Human Macrophage Foam Cell Formation and Coronary Atherosclerosis Molecular Cardiology

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- (cid:1) 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 (cid:1) 0.6 versus 15.4 (cid:1) 1.1 and 20.7 (cid:1) 1.5 pmol/L, respectively; P (cid:2) 0.0001). Immunoreactive salusin- (cid:1) and - (cid:2) were detected in human coronary atherosclerotic plaques, with dominance of salusin- (cid:2) 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- (cid:1) and increased by salusin- (cid:2) . Salusin- (cid:1) significantly reduced ACAT-1 expression in a concentration-dependent manner. In contrast, salusin- (cid:2) 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- (cid:1) and increased by salusin- (cid:2) ; however, neither salusin- (cid:1) nor salusin- (cid:2) affected scavenger receptor A function assessed by [ 125 I]acetylated low-density lipoprotein endocytosis or scavenger receptor class A and ATP-binding cassette transporter A1 expression. 37 patients with stable effort angina pectoris (26 men and 11 women 46 to 80 years old), 40 patients with mild hypertension (140 to 159 over 90 to 99 mm Hg) without chest pain (28 men and 12 women 40 to 91 years old), and 55 healthy volunteers (35 men and 20 women 20 to 90 years of age) who were free from hypertension, diabetes mellitus, hyperlipidemia, and ischemic heart disease and were taking no medications. Patients with congestive heart failure were excluded from the study, because we have found decreased levels of serum salusin- (cid:1) in these patients. Human coronary artery samples were collected from 4 patients with ACS (2 men and 2 women 40 to 76 years of age) at autopsy. The study was approved by the Ethics Committee of Showa University. The present study examined the potential roles of these peptides in atherosclerosis. Early events of atherosclerosis (foam cell formation) were oppositely influenced by salusin- (cid:1) and - (cid:2) with in vitro assays of primary human monocyte-derived macrophages. Salusin- (cid:1) suppressed foam cell formation via downregulation of acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1), whereas salusin- (cid:2) upregulated ACAT-1 to enhance foam cell formation. The in vitro observations have clinical relevance in that immunoreactive salusin- (cid:1) and - (cid:2) were detected in human coronary atherosclerotic plaques, with dominance of salusin- (cid:2) in vascular smooth muscle cells and fibroblasts. Serum salusin- (cid:1) 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 (cid:1) 0.6 versus 15.4 (cid:1) 1.1 and 20.7 (cid:1) 1.5 pmol/L, respectively; P (cid:2) 0.0001). Furthermore, in 60 patients with acute coronary syndrome, serum salusin- (cid:1) levels were decreased in accordance with the severity of coronary atherosclerotic lesions. These data suggest that salusin- (cid:2) may contribute to the pathogenesis of atherosclerosis. Salusin- (cid:1) could be a candidate biomarker for atherosclerosis and a therapeutic target for the prevention of atherosclerotic cardiovascular diseases. Prospective studies of salusins that examine relationships with other risk factors and outcomes over time may be warranted.