Deletion of Drp1 in macrophages exacerbated post-infarct left ventricular remodeling, leading to decreased ejection fraction and increased LV diameter in mice.
Does macrophage-specific Drp1 deletion or inhibition exacerbate post-infarct left ventricular remodeling in a mouse model of myocardial infarction?
Macrophage Drp1 is essential for mitochondrial quality control and protects against adverse left ventricular remodeling and inflammation following myocardial infarction.
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Abstract Aim Ischemic heart disease is a leading cause of death worldwide, and heart failure after myocardial infarction (MI) is a growing issue in an ageing society. Macrophages play a central role in left ventricular (LV) remodeling after MI. Mitochondria consistently change their morphology, including fission and fusion; however, the role of these morphological changes, particularly in macrophages, remains unknown. This study investigated the role of dynamin-related protein 1 (Drp1), a key mediator of mitochondrial fission, in macrophages and its involvement in the mechanisms of left ventricular remodeling after myocardial infarction (MI). Methods and Results This study utilized genetically altered mice lacking Drp1 in Lysozyme M-positive cells (Drp1-KO) to elucidate the specific role of macrophage Drp1 in post-infarct LV remodeling. Deletion of Drp1 in macrophages exacerbated LV remodeling, underpinned by reduced ejection fraction and increased LV diameter, which resulted in a poor prognosis after MI. Histological analysis indicated increased fibrosis and sustained macrophage accumulation in the infarcted hearts of Drp1-KO mice. Blockade of Drp1 in macrophages decreased mitochondrial fission and impaired mitophagy, leading to the subsequent release of mitochondrial DNA (mtDNA) into the cytosol and the induction of inflammatory cytokines. This induction was abrogated by the 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 the Drp1 inhibitor Mdivi-1. Conclusion Macrophage Drp1 plays a critical role in the pathobiology of post-infarct LV remodeling, particularly in mitochondrial quality control mechanisms. Macrophage Drp1 could be a novel therapeutic molecule to mitigate the progression of LV remodeling and consequent heart failure after MI.
Kondo et al. (Wed,) reported a other. Deletion of Drp1 in macrophages exacerbated post-infarct left ventricular remodeling, leading to decreased ejection fraction and increased LV diameter in mice.