Abstract 241: Cardiac TIMP-4 Dictates cardiomyocyte contractility and differentiation of embryonic stem cells into cardiomyocytes

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The remarkable nature of cardiomyocytes for contractility is attributed to the extracellular matrix which is maintained by the balance between MMPs (Matrix Metalloproteases) and TIMPs (Tissue Inhibitors of Matrix Metalloproteases). Any deviation from this delicate balance of MMP/TIMP is a hallmark of cardiovascular pathologies including myocardial infarction (MI). TIMP4, which is the least studied molecule, is deficient in failing hearts and mice lacking TIMP4 show poor regeneration capacity after MI. Therefore, we hypothesize that TIMP4 helps in cardiac regeneration by alleviating contractility and inducing the differentiation of cardiac progenitor cells into cardiomyocytes. To validate this hypothesis, we transfected cardiomyocytes with TIMP4 and TIMP4-siRNA and observed that there was increase in contractility in the TIMP4 transfected cardiomyocytes as compared to siRNA-TIMP4 transfected cardiomyocytes. To explain this we looked into the calcium channel genes and found increase in the expression of serca2a (sarcoplasmic reticulum calcium ATPase2a) in the TIMP4 transformed myocytes. Serca2a is tightly regulated by mir122a and we found decrease in the expression of mir122a in the TIMP4 transfected cells as compared to the TIMP4-siRNA cells. To observe the effect of TIMP4 in differentiation of cardiac progenitor cells we treated mouse embryonic stem cells with cardiac extract and cardiac extract minus TIMP4 (using TIMP4 monoclonal antibody). The cells treated with cardiac extract showed cardiac phenotype in terms of Ckit+, GATA4+ and Nkx2.5 expression. This is a novel report on the influence of TIMP4 on contractility and inducing the differentiation of stem cells to cardiomyocytes. In view of the failure of MMP9 inhibitors for cardiac therapy in clinical trials, TIMP4 provides and alternative approach, being an indigenous molecule, a natural inhibitor of MMP9 and efficient ROS scavenger.

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