Ablation of MMP9 ameliorates epigenetic modifications and mitigates diabetic cardiomyopathy

Abstract

Mutation of Insulin2 gene (orthologous to human Insulin) activates latent matrix metalloproteinase‐9 (MMP9) that fosters cardiomyopathy. Epigenetic modifications such as DNA methylation through DNA methyl transferases (DNMTs) and histone de‐acetylation by HDAC play crucial role in cardiac dysfunction. However, the epigenetic signature of MMP9 in diabetic hearts is unclear. We hypothesize that abrogation of MMP9 attenuates DNA methylation and histone de‐acetylation in diabetic hearts and ameliorates contractile dysfunction. To test the hypothesis, we created double knock out (DKO: Ins2+/−/MMP9−/−) mice by targeted deletion of MMP9 in Ins2+/− Akita, and determined the levels of DNMT‐1, HDAC, H3K9 and sarco‐endoplasmic reticulum ATPase‐2a (serca‐2a) in WT (C57BL/6J), Ins2+/− (Akita) and DKO hearts by RT‐QPCR, Western blot and confocal microscopy. We also measured contractility of cardiomyocytes using Ion‐optics device. The results revealed that DNMT‐1, HDAC and H3K9 are robust in Akita but alleviated in DKO hearts. Conversely, serca‐2a is down regulated in Akita but induced in DKO. The rate of contraction and relaxation (±dL/dt) is improved in DKO as compared to Akita. We conclude that targeted deletion of MMP9 ameliorates diabetic cardiomyopathy through epigenetic modifications.