Omentin-1 Modulates Macrophage Function via Integrin Receptors αvβ3 and αvβ5 and Reverses Plaque Vulnerability in Animal Models of Atherosclerosis.

Xuze Lin,Yan Liu,Shiwei Yang,Jinxing Liu,Yan Sun,Mengyue Yu,Jie Yang,Liu Pan,Qiaoyu Shao,Zhijian Wang,Jiaqi Yang,Yujie Zhou

doi:10.3389/fcvm.2021.757926

Abstract

Backgrounds: Omentin-1 is a novel cytokine that is primarily released by the epicardial adipose tissue. Molecular structure analysis revealed that it contained a fibrinogen-like domain. Clinical studies have demonstrated that the expression of omentin-1 is tightly associated with the development of cardiovascular diseases, but the receptor by which omentin-1 modulates macrophage function has not been identified yet.Objective: This study sought to investigate the effect of omentin-1 on already-established atherosclerosis (AS) lesions in both ApoE−/− and Ldlr−/− mice and further, study its underlying mechanisms.Methods and Results: We investigated the effect of omentin-1 on the plaque phenotype by implanting a minipump in ApoE−/− and Ldlr−/− mice. In vivo studies showed that the infusion of omentin-1 increased the collagen content and mitigated the formation of the necrotic core in both animal models. Immunohistochemistry and immunofluorescence analysis revealed that omentin-1 suppressed inflammatory cytokines expression, macrophage infiltration, and apoptosis within the plaque. An immunoprecipitation experiment and confocal microscopy analysis confirmed the binding of omentin-1 to the integrin receptors αvβ3 and αvβ5. The cell studies demonstrated that omentin-1 suppressed the apoptosis and inflammatory cytokines expression induced by the oxidized low-density lipoprotein in the macrophage. In addition, omentin-1 promoted the phosphorylation of the integrin-relevant signaling pathway as well as the Akt and AMPK in the macrophage. The addition of the inhibitor of the integrin receptor or interfering with the expression of the integrin subunit αv (ITGAV) both significantly abrogated the bioeffects induced by omentin-1. A flow cytometry analysis indicated that the antibodies against αvβ3 and αvβ5 had a competitive effect on the omentin-1 binding to the cell membrane.Conclusions: The administration of adipokine omentin-1 can inhibit the necrotic cores formation and pro-inflammatory cytokines expression within the AS lesion. The mechanisms may include the suppression of apoptosis and pro-inflammatory cytokines expression in the macrophage by binding to the integrin receptors αvβ3 and αvβ5.

Highlights

Coronary artery atherosclerosis (AS), which is characterized by the formation of an atherosclerotic lesion in the lumen epicardial arteries, frequently induces the stenosis of nourishing vessels of the myocardium and eventually gives rise to the myocardial ischemia [1]
After being treated by flag-tagged omentin-1 for another 3 weeks, the omentin-1 concentration in the plasma of the mice was measured by enzyme-linked immunoassay (ELISA) analysis, and the retention of omentin-1 in their aortic root lesion was examined by immunofluorescence analysis
The result of the ELISA showed that the intravenous infusion of exogenous omentin-1 significantly elevated the plasma omentin-1 level in the ApoE−/− mice and Ldlr−/− mice (Tables 3, 4)

Summary

Introduction

Coronary artery atherosclerosis (AS), which is characterized by the formation of an atherosclerotic lesion in the lumen epicardial arteries, frequently induces the stenosis of nourishing vessels of the myocardium and eventually gives rise to the myocardial ischemia [1]. Myocardial infarction is majorly caused by acute coronary syndrome (ACS), and plaque vulnerability is considered to play an important role in the induction of ACS. Many studies have demonstrated that macrophage infiltration, coupled with its apoptosis and inflammatory cytokine secretion, contributes to plaque instability and leads to plaque rupture [2, 3]. Several in vivo and in vitro studies revealed that the adipose tissue abundantly secretes bioactive molecules, which are termed adipokines, and impacts the metabolism profile of adjacent and remote organs by the paracrine and endocrine pathways [5]. Omentin-1, which is an adipokine mainly expressed by the visceral and epicardial adipose tissue (EAT), is composed of 313 amino acids and is considered to be a hydrophilic protein. Gaborit et al reported that the expression level of omentin-1 in the EAT is 12-fold higher than that in subcutaneous fats, and, surprisingly, our previous research indicated that the omentin expression is much lower in the EAT adjacent to the coronary stenotic segments [6, 7]

Methods

Results

Conclusion