Cardiomyocyte TRPV4 deletion preserves cardiac function following pressure overload‐induced pathological hypertrophy independent of cardiac fibrosis

Abstract

Left ventricular hypertrophy is compensatory adaptive response towards physical stimuli. However, prolonged changes in hemodynamic pressure due to pathological insults disrupts the electrical and bio-mechanical coupling between cardiomyocytes which leads to heart failure. Previous studies have demonstrated the role of soluble factors in the regulation of cardiomyocyte function, however, mechanosensor and mechanotransduction pathways in cardiomyocytes are remain unknown. We have recently shown that global deletion of mechanosensitive, transient receptor potential vanilloid 4 ion channel (TRPV4) preserves cardiac function and structure via reducing cardiac fibrosis after MI. Here we investigated cardiomyocyte specific role of TRPV4 following pressure overload induced hypertrophy. First, we found that TRPV4 expression is increased following pressure overload induced hypertrophy in wildtype (WT) mice. Global deletion of TRPV4 preserved myocardial structure and function compared to WT after 28 days of TAC. To understand the cardiomyocyte TRPV4 role, we have generated cardiomyocyte specific TRPV4 knockout mice (TRPV4CMKO) by crossing TRPV4lox/lox with Myh6cre mice. The littermates were confirmed for TRPV4 deletion in cardiomyocytes through genotyping and Real time PCR in tail snips and isolated cardiomyocytes. Next, we subjected the TRPV4lox/lox and TRPV4CMKO to TAC and then measured cardiac function. After 28 days of TAC, absence of TRPV4 in cardiomyocyte preserved the cardiac function compared to TRPV4lox/lox animals. Surprisingly, histological analysis revealed increased cardiac hypertrophy (cardiomyocyte cross sectional area) and cardiac fibrosis in TRPV4CMKO mice compared to TRPV4lox/lox mice or sham controls. Taken together our results suggest that cardiomyocyte specific deletion of TRPV4 preserves cardiac function despite of increased pathological remodeling of the heart and identify TRPV4 as new therapeutic target for the heart failure.