Abstract 124: Impact of Salusin-alpha and -beta on Human Macrophage Foam Cell Formation and Coronary Atherosclerosis
Background: Human salusins, related bioactive polypeptides with mitogenic effects on vascular smooth muscle cells (VSMCs) and fibroblasts as well as roles in hemodynamic homeostasis, may be involved in the etiology of coronary atherosclerosis. Macrophage foam cell formation, characterized by cholesterol ester (CE) accumulation, is modulated by scavenger receptor (SR), acyl-CoA:cholesterol acyltransferase-1 (ACAT1), and ATP-binding cassette transporter A1 (ABCA1).
Methods and Results: Serum levels of salusin-alpha were negatively correlated with maximum intima-media thickness in the carotid artery in 71 middle-aged men (r=−0.29, p<0.02). Serum salusin-alpha levels were decreased in 60 patients with acute coronary syndrome (ACS) as compared with 53 healthy volunteers (3.6+/−0.6 vs 21.7+/−1.5 pM, p<0.0001), and became significantly lower in accordance with the severity of coronary atherosclerotic lesions among ACS patients. Immunoreactive salusin-alpha and salusin-beta were detected in human coronary atherosclerotic plaques, with dominance of salusin-beta in VSMCs and fibroblasts. After 7 days in primary culture, acetylated LDL-induced CE accumulation in human monocyte-derived macrophages was significantly decreased by salusin-alpha and increased by salusin-beta. Salusin-alpha significantly reduced ACAT1 expression in a concentration-dependent manner. In contrast, salusin-beta significantly increased ACAT1 expression, with a maximal effect at 0.6 nM (2.1-fold increase), which was abolished by G protein, c-Src tyrosine kinase, protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) kinase inhibitors. ACAT activity and ACAT1 mRNA levels also were significantly decreased by salusin-alpha and increased by salusin-beta. However, neither salusin-alpha nor salusin-beta affected SR class A function assessed by [125I]acetylated LDL endocytosis or ABCA1 expression.
Conclusions: Our results suggest that the two salusin isoforms have opposite effects on foam cell formation in human monocyte-derived macrophages. In contrast to salusin-alpha as a negative risk factor for atherosclerosis, salusin-beta may participate in atherogenesis by ACAT1 up-regulation via G protein/c-Src/PKC/MAPK pathway.