MMP9 inhibition increases autophagic flux in chronic heart failure

Abstract

An increased matrix metalloprotease 9 (MMP9) during post‐myocardial infarction (post‐MI) exacerbates ischemia‐induced chronic heart failure (CHF). MMP9 abrogation is cardioprotective during post‐MI remodeling, however, whether MMP9 abrogation protects the heart via upregulation of autophagic activity is unknown. This study aimed to determine whether the MMP9 inhibition upregulates cardiac autophagic flux during post‐MI CHF in rats. Sprague‐Dawley rats underwent either Sham or coronary artery ligation, 6–8 weeks prior to being treated with MMP9‐inhibitor for 7 days, followed by cardiac autophagic flux measurement using lysosomal inhibitor BafilomycinA1. Further, autophagic flux was measured in vitro by treating H9c2 cardiomyocytes with two independent pharmacological MMP9 inhibitors, Salvianolic‐Acid‐B (SalB) or MMP9‐inhibitor‐I and CRISPR/cas9–mediated MMP9 genetic ablation. CHF rats showed cardiac infarct, significantly increased left‐ventricular end diastolic pressure (LVEDP), and increased MMP9 activity and fibrosis in the peri‐infarct areas of left‐ventricular myocardium. The autophagic markers LC3B‐II and p62 measurement with lysosomal inhibition showed decreased autophagic activity in the peri‐infarct myocardium. Treatment with SalB for 7 days in CHF rats decreased MMP9 activity, cardiac fibrosis, and increased autophagic flux in the peri‐infarct myocardium. As an in vitro corollary study, measurement of autophagic flux in H9c2 cardiomyocytes showed that pharmacological inhibition or genetic ablation of MMP9 upregulates autophagic flux. These data are consistent with our observations that MMP9 inhibition upregulates autophagic flux in the heart of rat with CHF. In conclusion, the results in this study suggest that the beneficial outcome of MMP9 inhibition on pathological cardiac remodeling is in part mediated by improved autophagic flux.Support or Funding InformationThis work was supported by American Heart Association Career Development Grant Award 19CDA34490029 to S.S. Nandi, and National Institutes of Health Grants R01‐DK‐114663, P01‐HL‐62222, and endowed McIntyre Professorship to K.P. Patel.