Activation of transient receptor potential vanilloid 4 is involved in pressure overload-induced cardiac hypertrophy

Abstract

Previous studies, including our own, have demonstrated that transient receptor potential vanilloid 4 (TRPV4) is expressed in hearts and implicated in cardiac remodeling and cardiac dysfunction. However, the effects of TRPV4 on pressure overload-induced cardiac hypertrophy remain unclear. In this study, we found that TRPV4 expression was significantly increased in mouse hypertrophic hearts, human failing hearts, and neurohormone-induced hypertrophic cardiomyocytes. Deletion of TRPV4 attenuated transverse aortic constriction (TAC)-induced cardiac hypertrophy, cardiac dysfunction, fibrosis, inflammation, and the activation of NF{kappa}B - NOD-like receptor pyrin domain-containing protein 3 (NLRP3) in mice. In vitro, TRPV4 inhibition decreased the neurohormone-induced cardiomyocyte hypertrophy and the increase of intracellular Ca2+ concentration. TRPV4 agonist triggered Ca2+ influx and evoked the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) but these effects were abolished by removing extracellular Ca2+ or TRPV4 inhibition. More importantly, TAC or neurohormone stimulation-induced CaMKII phosphorylation was significantly blocked by TRPV4 inhibition. Finally, we showed that CaMKII inhibition significantly inhibited the phosphorylation of NF{kappa}B induced by TRPV4 activation. Our results suggest that TRPV4 activation contributed to pressure overload-induced cardiac hypertrophy. This effect was associated with upregulated Ca2+/ CaMKII mediated the activation of NF{kappa}B-NLRP3. Thus, TRPV4 may represent a potential therapeutic drug target for cardiac hypertrophy.