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

Abstract

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 (4.9Ϯ0.6 versus 15.4Ϯ1.1 and 20.7Ϯ1.5 pmol/L, respectively; PϽ0.0001). 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 monocytederived 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

Associations of serum salusin-alpha levels with atherosclerosis and left ventricular diastolic dysfunction in essential hypertension

“…So we speculated that serum salusin-alpha levels might be associated with both initial and advanced atherosclerosis. Shichiri et al 8 have shown that salusin-alpha suppresses foam cell formation in human monocyte-derived macrophages in acute coronary syndrome, contributing to its anti-atherosclerotic effect. Therefore, it is possible that decreased salusin-alpha may have a causal role in the process of atherosclerotic plaque formation.…”

“…It was reported that development of atherosclerosis may be accelerated by salusin-beta and suppressed by salusin-alpha via acyl-CoA cholesterol acyltransferase-1(ACAT-1) regulation in acute coronary syndrome. 8 Previous study 9 has shown that serum salusin-alpha levels are decreased and correlated negatively with maximum IMT in essential hypertensive patients.…”

Serum salusin-α levels in systemic lupus erythematosus and systemic sclerosis

“…Both the formation of macrophage foam cells and the development of atherosclerosis are suppressed by salusin-α (7). Serum salusin-α levels are also reported to be significantly lower in patients with coronary artery disease, and in hypertensive patients in whom the salusin-α level is inversely associated with carotid atherosclerosis (7)(8)(9).…”

“…Salusins mainly affect the cardiovascular system (5)(6)(7)(8). Salusin-β is the most hypotensive peptide: its infusion rapidly and profoundly decreases blood pressure (BP) and heart rate (5).…”

“…Yu et al (6) have reported that salusins may have important roles in myocardial growth and hypertrophy. Salusin-α and salusin-β show inverse actions on atherosclerosis due to their opposite regulatory effects on acyl-coenzyme A: cholesterol acyltransferases-1 (ACAT-1) (7). Both the formation of macrophage foam cells and the development of atherosclerosis are suppressed by salusin-α (7).…”