Anti-Atherogenic Effects of Vaspin on Human Aortic Smooth Muscle Cell/Macrophage Responses and Hyperlipidemic Mouse Plaque Phenotype

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.

β-Endorphin Mediates the Development and Instability of Atherosclerotic Plaques

“…Cells were incubated at 37°C in a 5% CO 2 humidified incubator for 3 days in RPMI-1640 medium containing 10% fetal bovine serum (FBS), 0.05 mg/mL streptomycin, 50 U/mL penicillin, and the indicated concentrations of β-endorphin in the presence of 150 ng/mL TPA to induce differentiation into macrophages. Subsequently, THP-1 monocyte-derived macrophages were incubated for 3 days in the absence of TPA prior to immunoblotting [2,[29][30][31][32][33][34].…”

“…Atherosclerosis is a chronic inflammatory response to injury of the arterial wall [1,2]. Vascular inflammation stimulates the expression of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, in endothelial cells (ECs).…”

“…ese effectors encourage monocyte adhesion and infiltration into the neointima lesion, followed by atheroma formation and subendothelial accumulation of lipid-laden macrophage foam cells [1,3]. Foam cell formation is characterized by intracytoplasmic accumulation of cholesterol ester and depends on the balance among the uptake of oxidized low-density lipoprotein (oxLDL) via CD36, cholesterol esterification by acyl-CoA:cholesterol acyltransferase-1 (ACAT-1), and the efflux of free cholesterol controlled by the ATP-binding cassette transporter A1 (ABCA1) [2,3]. Categorization of the macrophage phenotype as either pro-or anti-inflammatory (M1 and M2 phenotypes, respectively) has recently focused on atherosclerosis [2,4].…”

“…Foam cell formation is characterized by intracytoplasmic accumulation of cholesterol ester and depends on the balance among the uptake of oxidized low-density lipoprotein (oxLDL) via CD36, cholesterol esterification by acyl-CoA:cholesterol acyltransferase-1 (ACAT-1), and the efflux of free cholesterol controlled by the ATP-binding cassette transporter A1 (ABCA1) [2,3]. Categorization of the macrophage phenotype as either pro-or anti-inflammatory (M1 and M2 phenotypes, respectively) has recently focused on atherosclerosis [2,4]. In addition, the migration and proliferation of vascular smooth muscle cells (VSMCs) also contribute to the development of atheromatous plaques [1,2].…”

“…Categorization of the macrophage phenotype as either pro-or anti-inflammatory (M1 and M2 phenotypes, respectively) has recently focused on atherosclerosis [2,4]. In addition, the migration and proliferation of vascular smooth muscle cells (VSMCs) also contribute to the development of atheromatous plaques [1,2].…”