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TRPV4 Channel Deletion Improves Cardiac Remodeling Following Myocardial Injury via Modulation of MRTF‐A Pathway
Author(s) -
ADAPALA RAVI KUMAR,
Thoppil Roslin,
Cappelli Holly,
Luther Daniel,
Ohanyan Vahagn,
Luli Jordan,
Paruchuri Sailaja,
Chilian William,
Meszaros J,
Thodeti Charles
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.845.6
Subject(s) - mechanosensitive channels , trpv4 , cardiac fibrosis , myofibroblast , cardiac function curve , myocardial infarction , ventricular remodeling , fibrosis , chemistry , microbiology and biotechnology , activator (genetics) , myocardin , heart failure , pressure overload , medicine , endocrinology , transcription factor , biology , ion channel , cardiac hypertrophy , receptor , biochemistry , gene , serum response factor
Cardiac remodeling following myocardial injury involves the differentiation of cardiac fibroblasts (CF) into hypersecretory myofibroblasts. We have recently shown TRPV4, a mechanosensitive ion channel mediates CF differentiation through integration of mechanical and soluble signals. Here, we investigated the functional role of TRPV4 in cardiac remodeling following myocardial infarction (MI) or pressure overload (TAC), in wild type (WT) and TRPV4 knockout (KO) mice and the underlying molecular mechanisms. We found that TRPV4 KO mice to have improved survival rates compared to WT following TAC, but was insignificant after MI. Cardiac function analysis showed preserved ejection fraction in TRPV4 null mice, post MI and TAC surgeries. Further, TRPV4 null mice exhibited significantly less interstitial fibrosis compared to WT mice post‐MI or TAC. To explore the molecular mechanism downstream of TRPV4, we focused on myocardin‐related transcription factor‐A (MRTF‐A) which was shown to be activated in response to Rho mediated stress fiber formation. We found that both TGF‐b1 and pharmacological TRPV4 activator GSK1016790A induced MRTF‐A activation (nuclear translocation), which was abolished when TRPV4 was inhibited. Finally, a MRTF‐A inhibitor abolished TGF‐b1‐induced CF differentiation in WT CF. Taken together, these findings suggest that the TRPV4 channels mediate cardiac fibrosis through MRTF‐A pathway and the deletion of TRPV4 improves cardiac function and remodeling following myocardial injury possibly via down‐regulation of this mechanotranscription pathway.