Abstract 19387: Targeted Deletion of Mmp9 Mitigates Autophagy Mediated Contractile Dysfunction in Insulin2 Mutant Diabetic Mice

Abstract

Insulin mediated activation of MMP9 and myocardial autophagy fosters pathological cardiac remodeling, and targeted deletion of MMP9 improves contractility. We hypothesize that ablation of MMP9 mitigates autophagy mediated contractile dysfunction in diabetes. To test the hypothesis, we created Ins2+/- /MMP9-/- mice, where MMP9 gene is deleted from diabetic Ins2+/-. We measured the levels of LC3B-II and Atg3 (autophagy markers) in C57BL/6J, Ins2+/- and Ins2+/- /MMP9-/- hearts. The results revealed induction of both LC3B-II and Atg3 in Ins2+/-, which is mitigated in Ins2+/-/MMP9-/- (fold change in C57BL/6J, Ins2+/-, Ins2+/- /MMP9-/- for LC3B-II: 1; 4.5 ±0.3, 3.0± 0.2, and Atg3: 1, 2.5±0.2, 1±0.3, respectively). The down regulation of autophagy in Ins2+/-/MMP9-/- suggests that targeted deletion of MMP9 attenuates autophagy in diabetes. To assess the specific role of autophagy in contractility, we administered Mdivi-1 (autophagy blocker) into C57BL/6J (control) and Ins2+/- mice (50mg/Kg, i.p) for 7 days and determined the improvement in contractility (±dL/dt) of cardiomyocytes by Ion-Optics device. We found no significant difference in the rate of contraction (dL/dt) and relaxation (-dL/dt) in C57BL/6J untreated (dL/dt=160±13 and -dL/dt= -165± 15) and treated (dL/dt= 170±20 and -dL/dt= -165± 21) groups. However, there was significant improvement in ±dL/dt in Ins2+/- (untreated: dL/dt=100±10 and -dL/dt= -95± 12) and treated (dL/dt= 185± 17 and -dL/dt= -180± 14). These elicit a novel regulatory role of MMP9 in autophagy in diabetes. It also suggests that inhibition of autophagy improves contractility in diabetic hearts. In conclusion, targeted deletion of MMP9 mitigates autophagy mediated contractile dysfunction in diabetes.