Mdivi-1 alleviates cardiac fibrosis post myocardial infarction at infarcted border zone, possibly via inhibition of Drp1-Activated mitochondrial fission and oxidative stress

Mitochondrial division inhibitor 1(Mdivi-1) has been shown to play a beneficial role in a variety of diseases, mainly by inhibiting Drp1-mediated mitochondrial fission. The effects of Mdivi-1 on cardiac fibrosis at infarcted border zone area and its possible mechanism remain unclear. This study aimed to investigate the effects of Mdivi-1 on reactive cardiac fibrosis and cardiac function post myocardial infarction and its potential mechanisms. Mice were randomly divided into six groups (n = 9 for each group): Sham; Mdivi-1; MI 7d; MI 14d; MI 28d; MI 28d + Mdivi-1. The MI model was induced by ligation of LAD coronary artery. Mdivi-1 (1 mg/kg) was administered to mice every other day at a time from the second day until the sacrifice of the mice (total 14 injection of Mdivi-1). In vitro experiments, the effect of Mdivi-1 on TGF-β1-induced fibrosis-related pathophysiological changes of fibroblasts was examined in NIH3T3 cells. We found that Mdivi-1 significantly attenuated fibroblast activation, collagen production and fibrosis at infarcted border zone after MI, improved impaired heart function. Mechanistically, we observed that Mdivi-1 reduced the protein expression of P-Drp1-S616 and abnormal mitochondrial fission of cardiac fibroblasts in the infarcted border zone area. In addition, we found that the effects of Mdivi-1 partially relied on increasing the expression of Hmox1 and inhibiting oxidative stress. In conclusion, Mdivi-1 could attenuate cardiac fibrosis at infarcted border zone and improve impaired heart function partially through attenuation of Drp1-mediated mitochondrial fission. Moreover, inhibition of oxidative stress, which is possible due to the up-regulation of Hmox1, may be another potential mechanism of action of Mdivi-1. •Increased phosphorylation of Drp1 at Ser616 in fibroblasts at infarcted border zone after MI.•Mdivi-1 could attenuate cardiac fibrosis of infarcted border zone.•Changes of P-Drp1-S616 protein expression and mitochondrial fission mediate the effects of Mdivi-1.•Regulation of Hmox1 and ROS are involved in protective effects of Mdivi-1.