Inflammation, miRNA and autophagy in diabetes

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DESCRIPTION (provided by applicant): Despite the gigantic stride made towards understanding of diabetic complications, the molecular mechanism is unclear. Differential expression of miRNA is associated with diabetes mellitus (DM). The long term goal of the project is to understand the regulation of miRNA in DM. Inflammation induces tumor necrosis factor alfa (TNFa) and matrix metalloproteinase-9 (Mmp9), and attenuates interleukin-10 (IL-10) and miR-223. Also, myosin enhancer factor -2c (Mef2C: an inducer of miR-133(anti-hypertrophy and anti-fibrosis)) is down regulated and microtubule-associated protein1 light chain3 (LC3), autophagy related gene3 (Atg3) and beclin-1 (markers of autophagy) are induced. We reported that Mmp9 impairs contractility of cardiomyocytes and increases fibrosis, whereas ablation of Mmp9 improves contractility and up regulates miR-133. However, the role of Mmp9 and miR-133 axis in autophagy and DM is unknown. Our preliminary studies show that TNFa is induced and IL-10 and miR-223 are attenuated in diabetic hearts. Interestingly, TNFa is robust in hypertrophic cardiomyocytes. To investigate the mechanism of Mmp9 mediated regulation of miR-133 and autophagy in diabetes, we created double knock out (DKO) by deleting Mmp9 gene from diabetic Ins2+/- Akita mice. DKO (Ins2+/- /Mmp9-/-) mice revealed improvement in cardiac function, induction of Mef2C and miR-133, and inhibition of LC3 and Atg3 (autophagy). The miR- 133 mitigates myocardial Mmp9 in diabetes by targeting 3'UTR of Mmp9. In addition, treatment with miR- 133 and Mdivi-1(blocker of autophagy) improved cardiac function in diabetic Akita. The central hypothesis of the proposal is that inflammation activates Mmp9 that inhibits Mef2c and miR-133, and induces autophagy resulting into cardiac dysfunction in DM. We will test the hypothesis by the following three specific aims: Aim#1: To determine whether the inflammation induces TNFa and attenuates miR-233 and IL-10 in diabetes. Hypothesis: In diabetes, inflammation induces TNFa and down regulates miR-223 and IL-10. Aim# 2: To determine whether the cardiac fibrosis is due, in part, to activation of Mmp9 and inhibition of Mef2C and miR-133 in diabetes. Hypothesis: In diabetes, activation of Mmp9 attenuates Mef2c and miR-133, and induces cardiac fibrosis. Aim # 3: To determine whether the autophagy causes cardiac dysfunction in diabetes. Hypothesis: In diabetes, Mmp9 is robust and it induces autophagy causing cardiac dysfunction. These studies will unravel the roles of inflammation, miR-133 and -223, Mmp9 and autophagy in cardiac dysfunction in diabetes. It will also provide impetus to assess the therapeutic potential of miR- 133 and Mmp9 in diabetic cardiomyopathy.