Acetyltransferase p300 in myofibroblast differentiation and cardiac fibrosis

Cardiac fibrosis, a major cause of cardiovascular disease related deaths, contributes to the development of ventricular dysfunction, heart failure and arrhythmias. On a cell-molecular level, cardiac fibrosis is characterized by an excessive synthesis of extracellular matrix proteins in myocardial tissues by differentiated myofibroblasts. Mofibroblasts in affected hearts may originate from resident cardiac fibroblasts and vascular endothelial cells. However, epigenetic regulation of myofibroblast differentiation from these cell types and its contribution to cardiac fibrogenesis is enigmatic. Acetyltransferase p300 (ATp300), a nuclear phosphoprotein, is a crucial epigenetic regulator and coactivator for the regulation of genes involved in cellular growth and differentiation. Deregulated ATp300 is known to play a pivotal role in the development of numerous diseases. The goal of the present proposal is to determine the significance of epigenetic regulator ATp300 in differentiation of myofibroblasts from cells of different lineages and its impact in cardiac fibrogenesis. The present research goal is formulated based on our strong preliminary data that i) ATp300 is essential for elevated collagen synthesis in response to profibrotic signaling; ii) the levels of ATp300 are significantly elevated in fibrotic hearts and in myofibroblast differentiated from cells of different lineages; iii) ATp300 inhibitor blocks Angiotensin II-induced cardiac fibrosis and TGF--induced myofibroblast differentiation from resident cardiac fibroblasts and endothelial cells in vitro. The contributions of altered levels of ATp300 in myofibroblast differentiation of these cells in vivo and cardiac fibrogenesis are unknown. We hypothesize that epigenetic regulator ATp300 is essential for induction of myofibroblast differentiation from resident cardiac fibroblasts and vascular endothelial cells and development of cardiac fibrosis. To test this hypothesis, we proposed two specific aims: Specific Aim 1.To determine whether ATp300 is essential for induction of myofibroblast differentiation from resident cardiac fibroblasts and vascular endothelial cells in vitro. Specific Aim 2.To determine whether ATp300 is essential for myofibroblast differentiation from resident cardiac fibroblasts and vascular endothelial cells in vivo, and its contribution in cardiac fibrogenesis. This proposed study will provide novel insights into the epigenetic regulation of cardiac fibrosis and potential therapeutics of fibrosis associated with cardiovascular diseases.