Abstract 4122249: Deletion of macrophage dynamin-related protein 1 exacerbates left ventricular remodeling after myocardial infarction by impairing mitochondrial quality maintenance machinery

Background: Macrophage-mediated inflammation plays an important role in the healing process after myocardial infarction (MI). We have previously reported in macrophages that inhibition of dynamin-related protein 1 (Drp1), which induces mitochondrial fission, restrains skewing toward inflammatory phenotype. It is, however, obscure whether macrophage Drp1 promotes left ventricular (LV) remodeling after MI. Aims: The aim of this study is to elucidate the role of macrophage Drp1 in the mechanisms of LV remodeling after MI. Methods: C57Bl/6J mice specifically deficient Drp1 in Lysozyme-M + macrophages (Drp1KO) were created by Cre/loxP technology and underwent ligation of the left anterior descending coronary artery at 8 to 12 weeks of age. Results: Deletion of macrophage Drp1 decreased LV ejection fraction (38±14 vs. 23±9% at day 28. N=9, p<0.05) and increased LV diameter (LVDd/Ds 5.7±0.4/4.8±0.3 vs. 4.6±0.2/3.7±0.3mm at day 28, N=9, p<0.05) (Figure). Survival rates until 28 days after MI were significantly lower in Drp1KO mice (25 vs. 64%. N=24 and 33, p<0.05). Deletion of Drp1 led to sustained macrophage accumulation and fibrosis of infarcted tissues. TEM revealed that mitophagosomes are decreased in Drp1-deficient macrophages in infarcted hearts. In ex vivo cultured macrophages, siRNA-mediated knockdown of Drp1 impaired mitochondrial fission and LC3-dependent mitophagy. In these macrophages, inhibition of Drp1 by Mdivi-1 for 96 hr, but not for 24 hr, induced mitochondrial DNA (mtDNA) leakage to the cytosol accompanied by increased expression of inflammatory cytokines. Hypoxia and starvation, in addition to Mdivi-1, induced leakage of mtDNA and expression of inflammatory cytokines at 24 hr. These results suggest that impairment of mitochondrial quality maintenance machinery causes leakage of mtDNA that induces inflammation. Conclusions: Macrophage Drp1 protects the heart from sustained inflammation and adverse cardiac remodeling after MI. Drp1-LC3-mediated mitophagy could be a mechanism that maintains mitochondrial quality and prevents excessive inflammation after MI.