KDM3A inhibition modulates macrophage polarization to aggravate post-MI injuries and accelerates adverse ventricular remodeling via an IRF4 signaling pathway.

08:00 EDT 9th September 2019 | BioPortfolio

Summary of "KDM3A inhibition modulates macrophage polarization to aggravate post-MI injuries and accelerates adverse ventricular remodeling via an IRF4 signaling pathway."

It has been reported that KDM3A participates in several cardiovascular diseases through epigenetic mechanisms. However, its biological role post myocardial infarction (MI) has not been explored. Excessive and prolonged inflammation period can aggravate post-MI injuries and accelerates left ventricular (LV) remodeling. Previous studies have shown that macrophages play a momentous role in post-MI injuries by regulating the balance between the inflammatory phase. In this study, we aimed to demonstrate whether KDM3A could regulate the polarization of macrophages to affect the inflammatory response after myocardial infarction and whether targeting KDM3A could influence the prognosis of myocardial infarction and adverse LV remodeling. To explore the biological function of KDM3A and the underlying mechanisms, the loss of function experiments were designed in vitro and vivo. we analyzed the function of macrophages by a phagocytosis and migration assay and explored the polarization of macrophages. The expression of macrophage inflammation-related genes in the acute inflammatory phase and surface markers was detected by western blot and immunofluorescence assays. Echocardiography, Masson's trichrome staining and hematoxylin and eosin (H&E) staining were used to detect cardiac ventricular function. Our data showed that KDM3A is essential for the biological function of rat bone marrow macrophages (BMDMs), and KDM3A deficiency decreases the capacity for phagocytosis and migration, promoting M1 but restraining M2 macrophage phenotype polarization in vitro. Furthermore, we constructed MI models of male rats to verify that KDM3A deficiency could regulate macrophage polarization to aggravate the inflammatory response and accelerate LV remodeling in vivo. Among them, we confirmed that IRF4 is a downstream effector of the KDM3A-dependent pathway which could epigenetically influence the transcription of IRF4 by enhancing histone H3 lysine 9 di-methylation(H3K9me2) accumulation on the IRF4 gene proximal promoter region to modulate macrophage polarization. These results demonstrated that KDM3A plays an essential role in the cardiac repair process of post-MI and LV remodeling by modulating the macrophage phenotype, thereby suggesting a promising therapy to treat post MI injuries.


Journal Details

This article was published in the following journal.

Name: Cellular signalling
ISSN: 1873-3913
Pages: 109415


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