Abstract
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 Apoe−/− 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 Apoe−/− 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.
Highlights
Atherosclerosis is a chronic inflammatory disease arising from endothelial injury and accumulation of cholesterol-laden macrophage foam cells in the artery wall [1]
Macrophage foam cell formation is characterized by cholesterol ester accumulation that depends on the homeostatic balance among the uptake of oxidized low-density lipoprotein (LDL) via a scavenger receptor CD36, the efflux of free cholesterol controlled by ATP-binding cassette transporters A1 and G1 (ABCA1, ABCG1) and scavenger receptor class B type 1 (SRB1), and cholesterol esterification from excess free cholesterol by acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) [3]
Vaspin was expressed at high levels in atheromatous plaques and thick media (VSMCs) in human coronary arteries (Figure 1B)
Summary
Atherosclerosis is a chronic inflammatory disease arising from endothelial injury and accumulation of cholesterol-laden macrophage foam cells in the artery wall [1]. Vaspin inhibits the generation of reactive oxygen species (ROS) and the expression of pro-inflammatory molecules, such as interleukin 1, monocyte chemotactic protein 1, vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and selectin E in human vascular endothelial cells (ECs), and monocyte-EC adhesion [15,16,17]. Several lines of clinical evidence have shown that blood vaspin levels are elevated in patients with obesity, diabetes, metabolic syndrome, and coronary artery disease (CAD) [24,25,26,27]. We assessed the expression levels of vaspin in human coronary artery lesions in CAD patients, and the anti-atherogenic effects of vaspin on the inflammatory phenotype and foam cell formation in human macrophages, as well as the migration, proliferation, and ECM production in human aortic smooth muscle cells (HASMCs) in vitro. This study was performed as translational research, i.e., it is an attempt to study a candidate therapeutic target for atherosclerosis
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