Cardiomyocyte-specific expression of CYP2J2 prevents development of cardiac remodelling induced by angiotensin II

Cardiac remodelling is one of the key pathological changes that occur with cardiovascular disease. Previous studies have demonstrated the beneficial effects of CYP2J2 expression on cardiac injury. In the present study, we investigated the effects of cardiomyocyte-specific CYP2J2 expression and EET treatment on angiotensin II-induced cardiac remodelling and sought to determine the underlying molecular mechanisms involved in this process. Eight-week-old mice with cardiomyocyte-specific CYP2J2 expression (alpha MHC-CYP2J2-Tr) and wild-type (WT) control mice were treated with Ang-II. Ang-II treatment of WT mice induced changes in heart morphology, cardiac hypertrophy and dysfunction, as well as collagen accumulation; however, cardiomyocyte-specific expression of CYP2J2 attenuated these effects. The cardioprotective effects observed in alpha-MHC-CYP2J2-Tr mice were associated with peroxisome proliferator-activated receptor (PPAR)-gamma activation, reduced oxidative stress, reduced NF-kappa B p65 nuclear translocation, and inhibition of TGF-beta 1/smad pathway. The effects seen with cardiomyocyte-specific expression of CYP2J2 were partially blocked by treatment with PPAR-gamma antagonist GW9662. In in vitro studies, 11,12-EET(1 mu mol/L) treatment attenuated cardiomyocyte hypertrophy and remodelling-related protein (collagen I, TGF-beta 1, TIMP1) expression by inhibiting the oxidative stress-mediated NF-kappa B pathway via PPAR-gamma activation. Furthermore, conditioned media from neonatal cardiomyocytes treated with 11,12-EET inhibited activation of cardiac fibroblasts and TGF-beta 1/smad pathway. Cardiomyocyte-specific expression of CYP2J2 or treatment with EETs protects against cardiac remodelling by attenuating oxidative stress-mediated NF-kappa Bp65 nuclear translocation via PPAR-gamma activation.