Abstract Body: Background: Left ventricular hypertrophy (LVH) is an initially adaptive response to chronic volume or pressure overload but can ultimately progress to contractile dysfunction and heart failure. We previously showed that global or endothelial specific deletion of the transient receptor potential vanilloid 4 (TRPV4) channel protects against adverse cardiac remodeling after myocardial infarction (MI) or pressure overload (TAC) by inhibiting fibroblast activation or promoting coronary angiogenesis, respectively. However, the specific role of cardiomyocyte TRPV4 in pathological hypertrophy remains undefined.
Hypothesis: We hypothesized that cardiomyocyte specific TRPV4 deletion attenuates isoproterenol (ISO)–induced hypertrophy through a mechanism involving protein kinase G1 (PKG1) signaling.
Methods: Cardiomyocyte specific TRPV4 knockout mice (TRPV4^MKO; generated for the first time) and TRPV4^lox/lox littermate controls were treated with ISO (40 mg/kg/day) for 14 days to induce cardiac hypertrophy. Cardiac structure and function were assessed by echocardiography. Cardiac fibrosis was quantified using Masson’s Trichrome staining. To identify relevant signaling pathways, we analyzed single nucleus RNA sequencing datasets from patients with hypertrophic cardiomyopathy and healthy controls, focusing on PKG1 expression. Mechanistic studies were performed in AC16 human cardiomyocytes to examine the effects of TRPV4 inhibition and PKG1 blockade on hypertrophic signaling.
Results: ISO induced significant cardiac hypertrophy in TRPV4^lox/lox mice, whereas TRPV4^MKO mice were markedly protected. ISO induced interstitial fibrosis, however, was similar between genotypes. Echocardiography revealed reduced ejection fraction and fractional shortening in TRPV4^lox/lox mice, changes that were prevented in TRPV4^MKO mice. Single nucleus RNA sequencing demonstrated substantial downregulation of PKG1 in cardiomyocytes from patients with hypertrophic cardiomyopathy compared with healthy controls. In vitro, TRPV4 inhibition increased PKG1 expression and attenuated ISO induced hypertrophic responses in AC16 cells, whereas pharmacological PKG1 inhibition with KT5823 worsened hypertrophy.
Conclusion: These findings demonstrated that cardiomyocyte-specific deletion of TRPV4 mitigates adverse cardiac remodeling by modulating PKG1 signaling, identifying the TRPV4-PKG1 axis as a potential therapeutic target for heart failure.