TRPV4-dependent signaling pathways play essential regulatory roles in high salt-induced cardiac hypertrophy via autophagic alterations.

Abstract

Cardiac hypertrophy, initially referred to as an adaptive response, would gradually transit to decompensated states over time, contributing to hypertension, and ultimately heart failure under salt overload. The cellular and molecular mechanisms driving salt-induced cardiac hypertrophy, as well as the signaling pathways responsible for this shift from compensation to decompensation, still remain insufficiently understood. Transient receptor potential vanilloid 4 (TRPV4) is ubiquitously expressed in cardiomyocytes, participating in cardiac remodeling and dysfunction. This study investigated TRPV4-relevant mechanisms in salt-induced cardiac hypertrophy. Knockdown of TRPV4 with cardiac gene transfer of Lv-shTRPV4 attenuated salt-induced cardiac hypertrophy, ROS generation, perivascular fibrosis and Akt & mTOR phosphorylation in adult rats. The in vitro results suggest that exposing cardiomyocytes to high-salt induced a concentration-dependent increase in autophagy, which was initially a rising phase and later followed by a declining phase. Salt-induced autophagic activity was enhanced by inhibiting Class I PI3-Kinase (PI3KC1) with LY294002 or Akt with AZD5363, but got undermined by AMPK inhibition with Compound C (CC) or SIRT1 inhibition with EX-527. Additionally, blockade of PI3KC1/Akt pathway significantly attenuated high salt-induced ROS generation and cardiac hypertrophy, whilst blockade of AMPK/SIRT1 pathway exacerbated high salt-induced cardiac hypertrophy via ROS accumulation. Thus, both PI3KC1 and AMPK signaling pathways participate in salt-induced cardiac hypertrophy via shared upstream component of TRPV4: lower salt triggers AMPK, scavenges ROS, preventing cardiac hypertrophy, whilst higher salt activates PI3KC1 with opposite effects. Our findings illuminate potential therapeutic effects of interfering TRP-related channels on high salt-induced hypertrophy and other mechanical stretch force-associated diseases.