Fig. 7.
Schematic of mechanisms on EET-mediated signaling in response to cardiac hypertrophy and fibrosis. EETs inhibit cardiac hypertrophy by acting directly on cardiomyocytes through the PPAR-γ/oxidative stress/SERCA2a/ER stress pathway and interaction of Akt1 and AMPKα2β2γ1 (8, 13, 14). Moreover, EETs attenuate pro-fibrotic and pro-inflammatory responses of cardiomyocytes transmitted to cardiac fibroblasts and macrophages, respectively (13, 15). This study indicates that EETs inhibit cardiac fibrosis by inhibiting fibrotic response of cardiac fibroblasts, including inhibition of cardiac fibroblast activation, proliferation, migration, and collagen secretion. Mechanistically, EETs stimulate the NO/cGMP signaling pathway, which reduces Gα12/13 and subsequently inhibits RhoA/ROCK activation (Dashed lines represent previous findings and solid lines represent present findings).