GDF-15 Suppresses Atherosclerosis by Inhibiting oxLDL-Induced Lipid Accumulation and Inflammation in Macrophages.

Hong Huang,Yan Li,Xianying Wang,Le Xiao,Qiang Meng,Zhongli Chen,Hao Fu,Jingjing Yang,Kunmei Gong,Feng Zhang

doi:10.1155/2021/6497568

Abstract

The growth differentiation factor-15 (GDF-15) may be involved in atherosclerosis. However, the role of GDF-15 in atherosclerosis remains unclear. The main goal of this study was to verify the role and mechanism of GDF-15 in atherogenesis. We first compared the serum GDF-15 level between patients with coronary atherosclerosis and healthy people. And then one ApoE−/− mouse model of atherosclerosis was used to explore the effects of GDF-15 on oxidized low-density lipoprotein (oxLDL) accumulation, atherosclerosis-related gene expression, and lipid accumulation-related protein expression in mouse macrophages. As a result, the level of serum GDF-15 in patients with coronary atherosclerosis was significantly higher than that in healthy people. In the mouse model, GDF-15 expression was elevated in the core of plaque, and it was secreted mainly by the macrophages. In addition, GDF-15 decreased oxLDL-induced lipid accumulation and inflammation activation in macrophages. GDF-15 decreased the mRNA expressions of CD36, LOX1, and TLR4 that are associated with lipoprotein accumulation in macrophages. Further study showed that GDF-15 might suppress oxLDL-induced lipoprotein accumulation via inhibiting CD36 and LOX1 and decrease inflammation in macrophages by inhibiting TLR4. Thus, GDF-15 may suppress atherosclerosis and plaque formation by inhibiting lipoprotein accumulation and inflammation activation.

Highlights

Atherosclerosis is the leading cause of vascular diseases, including ischemic heart disease, ischemic stroke, and peripheral arterial disease [1]
We aimed to explore the role of growth differentiation factor-15 (GDF-15) in lipoprotein accumulation and inflammatory response in atherosclerosis. e serum GDF-15 level in atherosclerosis patients and healthy people and the expression and location of GDF-15 in the aorta atheromatous plaque in mice were detected first. en the effect of GDF-15 on lipoprotein accumulation and proinflammatory cytokines releasing in oxidized low-density lipoprotein treated macrophages was revealed
One previous atherosclerosis mouse model study demonstrated that GDF-15 deficiency attenuates early atherogenesis and improves plaque stability [12]. e clinical study suggested that a high level of GDF-15 is associated with coronary artery disease, a disease involving chronic inflammatory atherosclerosis [17]

Summary

Introduction

Atherosclerosis is the leading cause of vascular diseases, including ischemic heart disease, ischemic stroke, and peripheral arterial disease [1]. E sequestered lipoproteins induce an inflammatory response, and circulating monocytes are recruited to this site and differentiate into macrophages that can ingest sequestered lipoproteins, fighting against inflammation. Endothelium increases its permeability to lipoproteins, leading to the accumulation of lipoprotein in the arterial vessel wall. This process cannot clear lipoproteins but transforms macrophages to lipoprotein-laden foam cells, which can secrete various substances to initiate and promote atherosclerotic plaque formation. TGF-β and BMPs regulate the proliferation, differentiation, and survival of endothelial cells, smooth muscle cells, macrophages, and T cells through activating

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