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

  • Arch Biochem Biophys. 2022 Mar 30;718:109147. doi: 10.1016/j.abb.2022.109147.
Jie Ding  1 ,  Zhihao Zhang  1 ,  Sui Li  1 ,  Wei Wang  1 ,  Tingyi Du  1 ,  Qin Fang  2 ,  Yan Wang  3 ,  Dao Wen Wang  1
Affiliations
  • 1. Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan, China.
  • 2. Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan, China. Electronic address: [email protected].
  • 3. Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan, China. Electronic address: [email protected].
PMID: 35143784 DOI: 10.1016/j.abb.2022.109147
Abstract

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.

Keywords
Cardiac fibrosis; Hmox1; Mdivi-1; Mitochondrial fission; Myocardial infarction; Oxidative stress.
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