Abstract 5158: Opposite Effects of Salusins on the Development of Atherosclerotic Plaques
Background: Human salusin-α and -β are 2-related peptides processed from the same precursor, preprosalusin. Our previous studies in vitro showed that human macrophage foam cell formation is stimulated by salusin-β but suppressed by salusin-α (Circulation 2008;117;638 – 48). Thus we assessed the effects of salusin-α and -β on atherosclerotic plaque formation in vivo in apoE-KO mice. Further, we investigated the relationship between serum salusin-α levels and carotid atherosclerosis in patients with essential hypertension.
Methods and Results: Saline, salusin-α or -β (600 pmol/kg/h) was continously infused through osmotic minipumps into 13-week-old apoE-KO mice. Aortic atherosclerosis, oxidized LDL-induced cholesterol ester accumulation (foam cell formation), and its related gene expression in exudate peritoneal macrophages were determined. After 4-week infusion of salusin-β, atherosclerotic lesions were 2.6-times greater than vehicle controls, which paralleled 1.9-fold increase in foam cell formation and upregulation of scavenger receptors (CD36, scavenger receptor class A) and acyl-CoA:cholesterol acyltransferase-1 (ACAT1). In contrast, salusin-α decreased serum total cholesterol levels by 15% and foam cell formation by 68% partly due to ACAT1 downregulation. After 8-week infusion of salusin-α, atherosclerotic lesions were significantly suppressed by 54% compared with vehicle controls. Clinically, serum salusin-α levels were significantly lower in patients with essential hypertension than healthy volunteers (9.4±0.9 pM [n=70] vs 17.0±3.5 pM [n=20], P<0.005). In all subjects, serum salusin-α levels became significantly lower in accordance with the severity of carotid plaque score and intima-media thickness (P<0.05). Immunoreactive salusin-α expression was at trace levels in human carotid plaques.
Conclusins: We provided the first evidence that salusin-β accelerates atherosclerotic lesion development by upregulation of scavenger receptors and ACAT1 in apoE-KO mice. In contrast, salusin-α exerts anti-atherosclerotic effects by suppressing serum total cholesterol levels and ACAT1 expression. Decreased levels of salusin-α in circulating blood and vascular tissue have a close linkage with human atherosclerosis.