Regulation of Cardiac Fibroblast Function by MicroRNAs

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Cardiac fibrosis is an integral feature of structural remodeling that occurs in response to a variety of cardiopulmonary diseases and can be a consequence of endothelial injury. It can impair ventricular function, increase the risk for arrhythmias and contribute to heart failure development. Cardiac fibroblasts are important therapeutic targets because they become activated in response to stress and play a key role in fibrosis development. Efforts to develop therapies that specifically target fibroblasts are still at an early stage. Compared to traditional drug targets, microRNAs (miRNAs) offer novel mechanistic possibilities. So far, little is known about their role in cardiac fibroblasts. I have determined the miRNA expression pattern in adult rat ventricular fibroblasts and their dynamic regulation during fibroblast activation in vitro. MiRNA-1, a muscle-enriched miRNA that has so far been extensively studied in myocytes, is shown to be expressed in cardiac fibroblasts and markedly down-regulated upon activation. My preliminary data also show miRNA-ldependent negative regulation of fibroblast proliferation, transformation and protein expression of several predicted miRNA-1 targets that are involved in cell cycle regulation and fibrosis development. The long-term goal of my research is to gain a better understanding of the functional role and mechanisms of action of miRNAs in cardiac fibroblasts under physiological and pathophysiological conditions. The Specific Aims are: i) To identify miRNAs that are changed in their expression upon fibroblast activation in vitro and in vivo and to select candidate miRNAs for further investigation based on their expression profile and target predictions; 2) To delineate functional effects and mechanisms of action of miRNA-1 and other miRNAs in adult cardiac fibroblasts using gain- and loss-of-function approaches; 3) To determine the effects of fibroblast-restricted miRNA manipulation on prevention and/or reversal of cardiac fibrosis development in vivo. This project will provide novel and comprehensive insights into miRNAs in cardiac fibroblasts. The findings will provide a platform for future grant applications that will aim to fully delineate the effects of fibroblast-restricted miRNA manipulation in vivo, which may provide new therapeutic strategies.