Fig. 8

In cardiomyocytes, this study is the first to demonstrate that 20-HETE upregulates AT1 receptor expression, thereby amplifying the biological effects of Ang II. Concurrently, Ang II induces CYP4A expression through an AT1 receptor-mediated signaling pathway, promoting 20-HETE production. Subsequently, 20-HETE activates NOX2 and NOX4 via the GPR75 receptor, leading to excessive intracellular ROS generation and mitochondrial oxidative damage. The 20-HETE/GPR75 axis further mediates Ang II-induced intracellular Ca²⁺ overload, where elevated Ca²⁺ activate calcineurin (CaN) to form the Ca²⁺-CaN complex. This complex promotes NFAT3 dephosphorylation and nuclear translocation, thereby activating hypertrophy-associated gene expression and ultimately leading to cardiac hypertrophy.