Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.
Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo 142-8666, Japan.
Int J Mol Sci. 2018 Jun 11;19(6):1732. doi: 10.3390/ijms19061732.
Vaspin (visceral adipose tissue-derived serine protease inhibitor) was recently identified as a novel adipocytokine with insulin-sensitizing effects. Serum vaspin levels are reported either increased or decreased in patients with coronary artery disease. Our translational research was performed to evaluate the expression of vaspin in human coronary atherosclerotic lesions, and its effects on atherogenic responses in human macrophages and human aortic smooth muscle cells (HASMC), as well as aortic atherosclerotic lesion development in spontaneously hyperlipidemic mice, an animal model of atherosclerosis. Vaspin was expressed at high levels in macrophages/vascular smooth muscle cells (VSMCs) within human coronary atheromatous plaques. Vaspin significantly suppressed inflammatory phenotypes with nuclear factor κB down-regulation in human macrophages. Vaspin significantly suppressed oxidized low-density lipoprotein-induced foam cell formation with CD36 and acyl-coenzyme A: cholesterol acyltransferase-1 down-regulation and ATP-binding cassette transporters A1 and G1, and scavenger receptor class B type 1 up-regulation in human macrophages. Vaspin significantly suppressed angiotensin II-induced migration and proliferation with ERK1/2 and JNK down-regulation, and increased collagen production with phosphoinositide 3-kinase and Akt up-regulation in HASMCs. Chronic infusion of vaspin into mice significantly suppressed the development of aortic atherosclerotic lesions, with significant reductions of intraplaque inflammation and the macrophage/VSMC ratio, a marker of plaque instability. Our study indicates that vaspin prevents atherosclerotic plaque formation and instability, and may serve as a novel therapeutic target in atherosclerotic cardiovascular diseases.
内脏脂肪组织丝氨酸蛋白酶抑制剂（vaspin）最近被鉴定为一种具有胰岛素增敏作用的新型脂肪细胞因子。在患有冠状动脉疾病的患者中，血清 vaspin 水平报告增加或减少。我们的转化研究旨在评估 vaspin 在人冠状动脉粥样硬化病变中的表达及其对人巨噬细胞和人主动脉平滑肌细胞（HASMC）的动脉粥样形成反应的影响，以及自发性高脂血症小鼠（动脉粥样硬化的动物模型）主动脉粥样硬化病变的发展。Vaspin 在人动脉粥样硬化斑块中的巨噬细胞/血管平滑肌细胞（VSMC）中高表达。Vaspin 通过下调核因子κB，显著抑制人巨噬细胞的炎症表型。Vaspin 通过下调 CD36 和酰基辅酶 A：胆固醇酰基转移酶-1，上调 ATP 结合盒转运体 A1 和 G1，以及清道夫受体 B 型 1，显著抑制氧化型低密度脂蛋白诱导的泡沫细胞形成，在人巨噬细胞中。Vaspin 通过下调 ERK1/2 和 JNK，上调磷酸肌醇 3-激酶和 Akt，显著抑制血管紧张素 II 诱导的 HASMC 迁移和增殖。慢性输注 vaspin 到小鼠中可显著抑制主动脉粥样硬化病变的发展，斑块内炎症和巨噬细胞/VSMC 比值显著降低，这是斑块不稳定的标志物。我们的研究表明，vaspin 可预防动脉粥样硬化斑块的形成和不稳定，可能成为动脉粥样硬化性心血管疾病的新治疗靶点。
