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

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.

The Complex Roles of Adipokines in Polycystic Ovary Syndrome and Endometriosis

“…This protein reduces oxidative stress, inflammation and programmed cell death [ 38 ]. Omentin-1 receptors, αvβ3 and αvβ5 integrins, have been identified in macrophages [ 39 ]. The plasma levels of this adipokine are decreased in women with PCOS, suggesting a role of omentin-1 in this disease [ 40 ].…”

Intelectin-1 binds and alters the localization of the mucus barrier–modifying bacterium Akkermansia muciniphila

“…This suggests that ITLN1 may enhance innate immune activation by promoting bacterial phagocytosis in addition to promoting mucus thinning. Although no ITLN1 receptor in immune cells has been identified, recent reports that the integrin receptors αvβ3 and αvβ5 ( Lin et al, 2021 ) and adiponectin receptor-1 ( Kobayashi et al, 2022 ) are potential ITLN1 receptors suggest that these proteins may contribute to increased phagocytosis of ITLN1-coated bacteria. However, further investigations are needed to extensively characterize the binding and signaling of ITLN1 in the context of interaction with bacterial targets and phagocytosis through these or other receptors.…”

The Role of Anti-Inflammatory Adipokines in Cardiometabolic Disorders: Moving beyond Adiponectin

“…Transgenic mice with the human omentin gene show decreased expression of pro-inflammatory cytokines via the stimulation of Akt [195]. Omentin-1 also suppresses macrophage aggregation, apoptosis, foam cell formation, and M1 phenotype [195][196][197]. Previously built atherosclerotic lesions are diminished by omentin-1 through reducing lipid content and necrotic core [195,196].…”

“…Omentin-1 also suppresses macrophage aggregation, apoptosis, foam cell formation, and M1 phenotype [195][196][197]. Previously built atherosclerotic lesions are diminished by omentin-1 through reducing lipid content and necrotic core [195,196]. Neointimal hyperplasia and VSMC proliferation are attenuated by omentin via the AMPK/ERK pathway [198].…”