Fig. 4.

Proposed mechanism underlying cardiac hypertrophy via TRPC/calcineurin/Nuclear factor of activated T-cells (NFAT) pathway. Activation of G_q-linked receptors by hypertrophic stimuli, such as ANG II, phenylephrine (PE), and endothelial-1 (ET-1), leads to the production of DAG and IP₃ via hydrolysis of PIP₂ by PLC activation. DAG activates TRPC3 and TRPC6, and IP₃-induced store depletion releases Ca²⁺ and subsequently activates TRPC channels. The resultant rise in [Ca²⁺]_i activates calcineurin (Cn) and causes translocation of NFAT, leading to the activation of hypertrophic gene expression, including TRPC1, 3, and 6. Upregulated TRPC channels will further activate the Cn/NFAT pathway, thereby perpetuating the TRPC-Ca²⁺-Cn/NFAT hypertrophy cascade (69, 151, 325).