TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals

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• 作者：Ravi K. Adapala^a ; ¹ ; Roslin J. Thoppil^a ; ¹ ; Daniel J. Luther^a ; Sailaja Paruchuri^b ; J. Gary Meszaros^a ; William M. Chilian^a ; Charles K. Thodeti^a ; ^{cthodeti@neomed.edu}
• 关键词：Calcium ; Cardiac remodeling ; Myocardial infarction ; Extracellular matrix ; TRPV4
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2013
• 出版时间：January, 2013
• 年：2013
• 卷：54
• 期：Complete
• 页码：45-52
• 全文大小：880 K

文摘

The phenotypic switch underlying the differentiation of cardiac fibroblasts into hypersecretory myofibroblasts is critical for cardiac remodeling following myocardial infarction. Myofibroblasts facilitate wound repair in the myocardium by secreting and organizing extracellular matrix (ECM) during the wound healing process. However, the molecular mechanisms involved in myofibroblast differentiation are not well known. TGF-¦Â has been shown to promote differentiation and this, combined with the robust mechanical environment in the heart, lead us to hypothesize that the mechanotransduction and TGF-¦Â signaling pathways play active roles in the differentiation of cardiac fibroblasts to myofibroblasts. Here, we show that the mechanosensitve ion channel TRPV4 is required for TGF-¦Â1-induced differentiation of cardiac fibroblasts into myofibroblasts. We found that the TRPV4-specific antagonist AB159908 and siRNA knockdown of TRPV4 significantly inhibited TGF¦Â1-induced differentiation as measured by incorporation of ¦Á-SMA into stress fibers. Further, we found that TGF-¦Â1-induced myofibroblast differentiation was dependent on ECM stiffness, a response that was attenuated by TRPV4 blockade. Finally, TGF-¦Â1 treated fibroblasts exhibited enhanced TRPV4 expression and TRPV4-mediated calcium influx compared to untreated controls. Taken together these results suggest for the first time that the mechanosensitive ion channel, TRPV4, regulates cardiac fibroblast differentiation to myofibroblasts by integrating signals from TGF-¦Â1 and mechanical factors.