Impact of salusin-α and -β on human macrophage foam cell formation and coronary atherosclerosis
Impact of salusin-α and -β on human macrophage foam cell formation and coronary atherosclerosis
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DOI：
10.1161/circulationaha.107.712539
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发表时间：
2008-02-05
期刊：
影响因子：
37.8
通讯作者：
Miyazaki, Akira
中科院分区：
文献类型：
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作者：
Watanabe, Takuya;Nishio, Kae;Miyazaki, Akira
背景-人类Salusins是一种相关的生物活性多肽，对血管平滑肌细胞和成纤维细胞具有促有丝分裂作用，并在血流动力学动态平衡中发挥作用，可能参与冠状动脉粥样硬化的起源。巨噬细胞泡沫细胞的形成受清道夫受体(胆固醇内流)、酰基辅酶A：胆固醇酰基转移酶-1(ACAT-1；由游离胆固醇转化而来的储存胆固醇酯)和三磷酸腺苷结合盒转运体A1(胆固醇外流)的调节。方法和结果：与40例轻度高血压患者和55名健康志愿者相比，冠状动脉造影证实的冠心病患者血清Salusin-α水平降低(分别为4.9/-0.6比15.4/-1.1和2 0.7+/-1.5pmol/L；P<；0.0001)。在人冠状动脉粥样硬化斑块中检测到Salusin-α和Salusin-β的免疫反应，其中Salusin-β在血管平滑肌细胞和成纤维细胞中占优势。原代培养7d后，Salusin-α可显著降低乙酰化低密度脂蛋白诱导的人单核巨噬细胞胆固醇酯蓄积，而Salusin-beta可使其升高。Salusin-α以浓度依赖的方式显著降低ACAT-1的表达。相反，Salusin-beta显著增加ACAT-1的表达2.1倍，在0.6nmol/L时作用最强。这些作用可被G蛋白、c-Src酪氨酸激酶、蛋白激酶C和丝裂原激活的蛋白激酶激酶抑制剂所消除。Salusin-α显著降低ACAT活性，上调ACAT-1mRNA水平，但Salusin-α和Salusin-beta均不影响清道夫受体A的功能，也不影响清道夫受体A类和ATP结合盒转运体A1的表达。结论：两种Salusin异构体对人单核细胞来源的巨噬细胞泡沫细胞的形成具有相反的作用。Salusin-β可加速动脉粥样硬化的发展，而salusin-α可通过调节ACAT-1抑制动脉粥样硬化的发展。
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-alpha levels were decreased in 173 patients with angiographically proven coronary artery disease compared with 40 patients with mild hypertension and 55 healthy volunteers (4.9 +/- 0.6 versus 15.4 +/- 1.1 and 20.7 +/- 1.5 pmol/L, respectively; P < 0.0001). Immunoreactive salusin-alpha and -beta were detected in human coronary atherosclerotic plaques, with dominance of salusin-beta in vascular smooth muscle cells and fibroblasts. After 7 days in primary culture, acetylated low-density lipoprotein - induced cholesterol ester accumulation in human monocyte-derived macrophages was significantly decreased by salusin-alpha and increased by salusin-beta. Salusin-alpha significantly reduced ACAT-1 expression in a concentration-dependent manner. In contrast, salusin-beta 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-alpha and increased by salusin-beta; however, neither salusin-alpha nor salusin-beta affected scavenger receptor A function assessed by [I-125] acetylated low-density lipoprotein endocytosis or scavenger receptor class A and ATP-binding cassette transporter A1 expression.Conclusions - Our results indicate that the 2 salusin isoforms have opposite effects on foam cell formation in human monocyte-derived macrophages. Development of atherosclerosis may be accelerated by salusin-beta and suppressed by salusin-alpha via ACAT-1 regulation.