Mmp9 inhibition increases autophagic flux in chronic heart failure

Shyam S. Nandi, Kenichi Katsurada, Neeru M. Sharma, Daniel R. Anderson, Sushil K. Mahata, Kaushik P. Patel

Research output: Contribution to journalArticlepeer-review

Abstract

Increased matrix metalloprotease 9 (MMP9) after myocardial infarction (MI) exacerbates ischemia-induced chronic heart failure (CHF). Autophagy is cardioprotective during CHF; however, whether increased MMP9 suppresses autophagic activity in CHF is unknown. This study aimed to determine whether increased MMP9 suppressed autophagic flux and MMP9 inhibition increased autophagic flux in the heart of rats with post-MI CHF. Sprague-Dawley rats underwent either sham surgery or coronary artery ligation 6-8 wk before being treated with MMP9 inhibitor for 7 days, followed by cardiac autophagic flux measurement with lysosomal inhibitor bafilomycin A1. Furthermore, autophagic flux was measured in vitro by treating H9c2 cardiomyocytes with two independent pharmacological MMP9 inhibitors, salvianolic acid B (SalB) andMMP9 inhibitor-I, and CRISPR/cas9-mediatedMMP9 genetic ablation. CHF rats showed cardiac infarct, significantly increased left ventricular end-diastolic pressure (LVEDP), and increasedMMP9 activity and fibrosis in the peri-infarct areas of left ventricular myocardium. Measurement of the autophagic markers LC3B-II and p62 with lysosomal inhibition showed decreased autophagic flux in the peri-infarct myocardium. Treatment with SalB for 7 days in CHF rats decreasedMMP9 activity and cardiac fibrosis but increased autophagic flux in the peri-infarct myocardium. As an in vitro corollary study, measurement of autophagic flux in H9c2 cardiomyocytes and fibroblasts showed that pharmacological inhibition or genetic ablation ofMMP9 upregulates autophagic flux. These data are consistentwith our observations thatMMP9 inhibition upregulates autophagic flux in the heart of rats with CHF. In conclusion, the results in this study suggest that the beneficial outcome ofMMP9 inhibition in pathological cardiac remodeling is in part mediated by improved autophagic flux.

Original languageEnglish (US)
Pages (from-to)1414-1437
Number of pages24
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume319
Issue number6
DOIs
StatePublished - Oct 2020

Keywords

  • Autophagic flux
  • Chronic heart failure
  • Matrix metalloprotease 9
  • Myocardial infarction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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