Objective: Human salusin-alpha and -beta are two-related peptides processed from the same precursor, preprosalusin. Our previous in vitro studies have shown that human macrophage foam cell formation is stimulated by salusin-beta but suppressed by salusin-alpha. Thus we investigated the effects of salusin-alpha and -beta on atherosclerotic plaque formation in vivo in apolipoprotein E-deficient (ApoE-/-) mice.
Methods: Saline (vehicle), salusin-alpha or -beta (0.6 nmol/kg/h) was continuously infused through osmotic mini-pumps into 13-week-old ApoE-/- mice for 8 weeks. Aortic atherosclerosis, oxidized LDL-induced cholesterol ester accumulation (foam cell formation), and its related gene expression in exudate peritoneal macrophages were determined.
Results: After 4-week infusion of salusin-beta, atherosclerotic lesions were 2.6 times greater than vehicle controls, which paralleled 1.9-fold increase in foam cell formation and up-regulation of scavenger receptors (CD36, scavenger receptor class A) and acyl-CoA: cholesterol acyltransferase-1 (ACAT1). In contrast, salusin-alpha decreased serum total cholesterol levels by 15% and foam cell formation by 68% associated with ACAT1 down-regulation. After 8-week infusion of salusin-alpha, atherosclerotic lesions were significantly suppressed by 54% compared with vehicle controls.
Conclusions: Our study provided the first evidence that salusin-beta accelerates the development of atherosclerotic lesions associated with up-regulation of scavenger receptors and ACAT1 in ApoE-/- mice. Whilst, salusin-alpha exerts anti-atherosclerotic effects by suppressing serum total cholesterol levels and ACAT1 expression.
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