Hypoxia Induces M2 Macrophages to Express VSIG4 and Mediate Cardiac Fibrosis After Myocardial Infarction

Abstract

M2 macrophage-mediated tissue repair plays an important role in acute myocardial infarction (AMI). Additionally, VSIG4, which is mainly expressed on tissue-resident and M2 macrophages, is crucial for the regulation of immune homeostasis; however, its effects on AMI remain unknown. In this study, we aimed to investigate the functional significance of VSIG4 in AMI using VSIG4 knockout and adoptive bone marrow transfer chimeric models. We also determined the function of cardiac fibroblasts (CFs) through gain-or loss-of-function experiments. We showed that VSIG4 promotes scar formation and orchestrates the myocardial inflammatory response after AMI, while also promoting TGF-β1 and IL-10. Moreover, we revealed that hypoxia promotes VSIG4 expression in cultured bone marrow M2 macrophages, ultimately leading to the conversion of CFs to myofibroblasts. Our results reveal a crucial role for VSIG4 in the process of AMI in mice and provide a potential immunomodulatory therapeutic avenue for fibrosis repair after AMI.

Identification of important genes related to anoikis in acute myocardial infarction

“…A previous study confirmed that in AMI, the expression of IL1R2 in M2‐type macrophages was elevated. 35 Kolbus et al. investigated two subsets of activated CD8+ T cells as predictors of AMI and ischemic stroke during a 15‐year follow‐up.…”

Macrophage-driven cardiac inflammation and healing: insights from homeostasis and myocardial infarction

“…In addition, a recent study found that hypoxia promotes M2 macrophage intracellular HIF-1α expression and nuclear translocation. It binds to the VSIG4 promoter region, mediating its expression, thereby enhancing the secretion of IL-10 and TGF-β by macrophages, regulating cardiac fibroblast proliferation, migration, and phenotypic transition, and promoting myocardial repair after infarction [ 130 ]. Not only in MI but also in other cardiovascular diseases, this pathway has been shown to affect macrophage function.…”

Cell or cell derivative-laden hydrogels for myocardial infarction therapy: from the perspective of cell types

“…In the proliferative phase, macrophages are polarized into M2-phenotype macrophages with anti-inflammatory property. 48,49 M2-phenotype macrophages secrete a variety of cytokines, such as TGF-β, IL-10, and VEGF, to promote tissue repair and angiogenesis. 50 At the maturation stage, the recruitment of macrophages ends.…”