Chronic infusion of salusin-α and -β exerts opposite effects on atherosclerotic lesion development in apolipoprotein E-deficient mice



      Human salusin-α and -β 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-β but suppressed by salusin-α. Thus we investigated the effects of salusin-α and -β on atherosclerotic plaque formation in vivo in apolipoprotein E-deficient (ApoE−/−) mice.


      Saline (vehicle), salusin-α or -β (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.


      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 up-regulation 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% associated with ACAT1 down-regulation. After 8-week infusion of salusin-α, atherosclerotic lesions were significantly suppressed by 54% compared with vehicle controls.


      Our study provided the first evidence that salusin-β accelerates the development of atherosclerotic lesions associated with up-regulation of scavenger receptors and ACAT1 in ApoE−/− mice. Whilst, salusin-α exerts anti-atherosclerotic effects by suppressing serum total cholesterol levels and ACAT1 expression.


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        • Pennings M.
        • Meurs I.
        • Ye D.
        • et al.
        Regulation of cholesterol homeostasis in macrophages and consequences for atherosclerotic lesion development.
        FEBS Lett. 2006; 580: 5588-5596
        • Miyazaki A.
        • Sakashita N.
        • Lee O.
        • et al.
        Expression of ACAT-1 protein in human atherosclerotic lesions and cultured human monocytes-macrophages.
        Arterioscler Thromb Vasc Biol. 1998; 18: 1568-1574
        • Shichiri M.
        • Ishimaru S.
        • Ota T.
        • Nishikawa T.
        • Isogai T.
        • Hirata Y.
        Salusins: newly identified bioactive peptides with hemodynamic and mitogenic activities.
        Nat Med. 2003; 9: 1166-1172
        • Suzuki N.
        • Shichiri M.
        • Akashi T.
        • et al.
        Systemic distribution of salusin expression in the rat.
        Hypertens Res. 2007; 30: 1255-1262
        • Sato K.
        • Koyama T.
        • Tateno T.
        • Hirata Y.
        • Shichiri M.
        Presence of immunoreactive salusin-α in human serum and urine.
        Peptides. 2006; 27: 2561-2566
        • Sato K.
        • Sato T.
        • Susumu T.
        • Koyama T.
        • Shichiri M.
        Presence of immunoreactive salusin-β in human plasma and urine.
        Regul Pept. 2009; 158: 63-67
        • Izumiyama H.
        • Tanaka H.
        • Egi K.
        • Sunamori M.
        • Hirata Y.
        • Shichiri M.
        Synthetic salusins as cardiac depressors in rat.
        Hypertension. 2005; 45: 419-425
        • Yu F.
        • Zhao J.
        • Yang J.
        • et al.
        Salusins promote cardiomyocyte growth but does not affect cardiac function in rats.
        Regul Pept. 2004; 122: 191-197
        • Hong-Xiao Y.
        • Li L.
        • Yan-Xia P.
        • et al.
        Salusins protect neonatal rat cardiomyocytes from serum deprivation-induced cell death through upregulation of GRP78.
        J Cardiovasc Pharmacol. 2006; 48: 41-46
        • Watanabe T.
        • Nishio K.
        • Kanome T.
        • et al.
        Impact of salusin-α and -β on human macrophage foam cell formation and coronary atherosclerosis.
        Circulation. 2008; 117: 638-648
        • Shiraishi Y.
        • Watanabe T.
        • Suguro T.
        • et al.
        Chronic urotensin II administration enhances macrophage foam cell formation and atherosclerosis in apolipoprotein E-knockout mice.
        J Hypertens. 2008; 26: 1955-1965
        • Xu G.
        • Watanabe T.
        • Iso Y.
        • et al.
        Preventive effects of heregulin-β1 on macrophage foam cell formation and atherosclerosis.
        Circ Res. 2009; 105: 500-510
        • Shichiri M.
        Reply to ‘Salusins: newly identified bioactive peptides with hemodynamic and mitogenic activities’.
        Nat Med. 2007; 13: 661-662
        • Watanabe T
        • Suguro T.
        • Kanome T.
        • et al.
        Human urotensin II accelerates foam cell formation in human monocyte-derived macrophages.
        Hypertension. 2005; 46: 738-744
        • Watanabe T.
        • Suguro T.
        • Sato K.
        • et al.
        Serum salusin-α levels are decreased and correlated negatively with carotid atherosclerosis in essential hypertensive patients.
        Hypertens Res. 2008; 31: 463-468