Abstract 24061: Targeting Trpv4 Channels Protects Heart From Pathological Remodeling Following Myocardial Infarction

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Abstract

Heart failure is one of the leading causes of death which is often characterized by pathological fibrosis. Cardiac remodeling following myocadial infarction is a multiphase reparative process which involves replacement of damaged tissue with physiological (reparative) fibrosis to form scar that limit the expansion of the infarct. Myofibroblasts are critical mediator of this reparative fibrosis, however, hyperactivation of these cells can cause pathological fibrosis leading to heart failure. We have previously demonstrated that the mechanosensitive ion channel TRPV4 (transient receptor potential vanilloid channel 4) regulates cardiac fibroblast differentiation into myofibroblasts. However, the physiological or translational significance of TRPV4 in cardiac remodeling following MI is unknown. To explore this, we have induced MI (permanent LAD ligation) in WT and TRPV4KO mice and measured cardiac function for 8 weeks. Separately, WT mice were given an orally active TRPV4 antagonist GSK2193874, immediately after MI surgery and followed for 5 weeks. 2D-echocardiography revealed that the cardiac function (ejection fraction and fractional shortening) is preserved post-MI in both TRPV4KO and GSK2193874-treated WT mice compared to either WT or vehicle treated mice. Further, we found reduced cardiac fibrosis at infarcted and remote zones in TRPV4KO and GSK2193874-treated WT mice compared to their MI counter parts. Furthermore, TRPV4KO hearts exhibited decreased cardiomyocyte apoptosis (TUNEL assay) and increased capillary density (CD31 staining) post-MI compared to WT hearts. Our results thus suggest that targeting TRPV4 protects heart from myocardial infarction-induced damage by preserving cardiac structure and function via reduced myocyte apoptosis, diminished fibrosis and increased revascularization, and identifies TRPV4 as a novel therapeutic target for heart failure.

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