Drp1-mediated mitochondrial fission protects macrophages from mtDNA/ZBP1-mediated sterile inflammation and inhibits post-infarct cardiac remodeling

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Abstract Background Ischemic heart disease is a leading cause of death worldwide, and heart failure after myocardial infarction (MI) is a growing issue in this aging society. Macrophages play central roles in left ventricular (LV) remodeling after MI. Mitochondria consistently change their morphology, including fission and fusion, but the role of these mitochondrial morphological changes, especially in macrophages, is unknown. This study aims to illuminate the effects and mechanisms of Dynamin-related protein 1 (Drp1), a molecule mediating mitochondrial fission, in macrophages for cardiac remodeling after MI. Methods This study utilized genetically altered mice lacking Drp1 in monocytes/macrophages (Drp1-KO) to elucidate the specific role of macrophage Drp1 in post-infarct LV remodeling. Results Deletion of Drp1 in macrophages exacerbated LV remodeling, including reduced ejection fraction and increased LV diameters, which resulted in decreased survival after MI. Histological analysis indicated increased fibrosis and sustained macrophage accumulation in Drp1-KO mice. Blockade of Drp1 in macrophages decreased mitochondrial fission and impaired mitophagy, leading to the subsequent release of mitochondrial DNA (mtDNA) to the cytosol and induction of inflammatory cytokines. This induction was abrogated by an autophagy inducer, Tat-beclin1, or siRNA-mediated knockdown of Z-DNA Binding Protein 1 (ZBP1). Deletion of ZBP1 in bone marrow-derived cells abrogated LV remodeling induced by Drp1 inhibitor, Mdivi-1. Conclusion Macrophage Drp1 plays a critical role in the pathobiology of LV remodeling after MI, especially mitochondria quality control mechanisms. Macrophage Drp1 could be a novel therapeutic molecule to mitigate the progression of LV remodeling and consequent heart failure after MI.

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