Abstract Wed036: Cardiomyocyte TRPV4 Deletion Mitigates Adverse Cardiac Remodeling Via Modulation of Protein Kinase G signaling

Left ventricular hypertrophy is an adaptive response to volume stress or pressure overload that can ultimately lead to contractile dysfunction and heart failure. Previously, we demonstrated that global or endothelial-specific deletion of transient receptor potential vanilloid 4 (TRPV4) channels protects the heart from adverse remodeling following myocardial infarction (MI) or pressure-overload (TAC), through inhibition of fibroblast differentiation or increased microvasculature, respectively. However, the specific role of the cardiomyocyte TRPV4 in cardiac remodeling remains unclear. To investigate this, we generated cardiomyocyte specific-TRPV4 knockout mice (TRPV4 MKO ) and subjected them to Isoproterenol (ISO; 30mg/kg/day) treatment for 14 days. Echocardiography analysis revealed that cardiac function is preserved in TRPV4 MKO mice compared to TRPV4 lox/lox mice. Further, cardiac hypertrophy and fibrosis were reduced in TRPV4 MKO mice compared to TRPV4 lox/lox mice, post-ISO treatment. Importantly, single-nucleus RNA sequencing analysis revealed significant downregulation of Protein kinase G1 (PKG1) in the hearts of hypertrophic cardiomyopathy patients compared to healthy controls. Consistent with this, TRPV4 inhibition increased PKG1 expression levels and prevented ISO-induced hypertrophy in AC16 human cardiomyocytes. Finally, pharmacological inhibition of PKG1 using KT5823 exacerbated hypertrophy in AC16 cells in response to ISO. Taken together, our results suggest that cardiomyocyte-specific deletion of TRPV4 mitigates adverse cardiac remodeling via downregulating PKG1 and identifying the TRPV4/PKG1 signaling as a potential therapeutic target for heart failure.