Research Project
10464881
PROJECT SUMMARY/ABSTRACT A common feature of heart failure (HF) is excessive extracellular matrix deposition by a specialized and differentiated fibroblast population, known as myofibroblasts, in response to cardiac injury. While myofibroblasts help to maintain the structural integrity of the injured heart and prevent ventricular wall rupture, persistence of myofibroblasts results in excessive fibrosis and subsequent cardiac decompensation. Therefore, identifying molecular mechanisms of myofibroblast differentiation in cardiac fibrosis could yield novel clinical targets to delay or reverse the development of HF. Recent evidence suggests metabolism may drive cellular differentiation through the modulation of epigenetic-modifying enzymes that enhance or silence genes associated with cellular differentiation. Altered metabolism changes the concentration of metabolites that act as substrates for epigenetically modifying enzymes, such as the changing levels of acetyl-CoA that alter the activity of histone acetyltransferases (HAT). Our preliminary data indicate that increased glycolytic rate is a key feature driving myofibroblast differentiation. We identified metabolic regulation of histone demethylation as a feature of myofibroblast differentiation and we now turn our sights to histone acetylation as an epigenetic modification permissive of myofibroblast gene expression. This proposal hypothesizes that increased acetyl-CoA biosynthesis is necessary for histone lysine acetylation by HATs during differentiation for the transcriptional activation of the myofibroblast gene program. This study seeks to identify novel therapeutic targets to mitigate the consequences of fibrosis in HF.
