Cytochrome P450 Epoxygenase 2J2 And Its Metabolites EETs Attenuate Ang ? Induced Cardiac Remodeling

Background and ObjectiveCardiac remodeling is described as changes in the size, shape and function of the heart resulting from cardiac overload and injury. Preventing cardiac remodeling is an important clinical issue due to its poor prognosis. CYP2J2 metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs). CYP2J2/EETs are abundantly expressed in human heart and are protective in cardiovascular system. However, the role of CYP2J2/EETs on cardiac remodeling has not been completely elucidated. Cardiomyocytes and cardiac fibroblasts exert important roles in cardiac remodeling. Therefore, we focused on the role of CYP2J2/EETs in cardiomyocytes and cardiac fibroblasts and sought to investigate mechanisms involved in Ang-II induced cardiac remodeling.Methods and ResultsEight-week old mice with cardiomyocyte-specific CYP2J2 expression (aMHC-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 a-MHC-CYP2J2-Tr mice were associated with PPAR-y activation, reduced oxidative stress, reduced NF-?B p65 nuclear translocation and inhibition of TGF-?1/smad pathway. The effects seen with cardiomyocyte-specific expression of CYP2J2 were partially blocked by treatment with PPAR-y antagonist GW9662. In in vitro studies,11,12-EET (1?mol/1) treatment attenuated Ang? induced cardiomyocyte hypertrophy and remodeling related proteins (collagen I, TGF-?1, TIMP1) expression, which were associated with PPAR-y activation and inhibition of oxidative stress-mediated NF-?B pathway. These benificial effects of 11,12-EET were partially blocked by PPAR-y antagonist GW9662. Moreover, NAC and EET exert similar and synergistic effects on cardiomyocytes hypertrophy, expression of cardiac remodeling proteins and p65 nuclear translocation induced by Ang-II. Above all,11,12-EET (1?mol/1) treatment attenuated cardiomyocyte hypertrophy and remodeling related protein (collagen I, TGF-?1, TIMP1) expression by inhibiting the oxidative stress-mediated NF-?B pathway via PPAR-y activation. Furthermore, Conditioned media from neonatal cardiomyocytes treated with 11,12-EET inhibited activation of cardiac fibroblasts and TGF-?1/smad pathway. In cardiac fibroblasts, Ang? induced cardiac fibroblasts activation, proliferation and migration connected with increased Ga12/13/RhoA/ROCK activity. These effects were inhibited by treatment with 11,12-EET. Moreover, either Ga12/13-specific siRNA or RhoA-specific siRNA exert similar effects of 11,12-EET. Furthermore, inhibition of Ga12/13 by 11,12-EET were blocked by NO/cGMP pathway inhibitors. These results demonstrated that 11,12-EET attenuated fibrotic response of cardiac fibroblasts by reducing G?12/13/RhoA/ROCK activity via NO/cGMP pathway activation.ConclusionsCardiomyocyte-specific expression of CYP2J2 or treatment with EETs protect against cardiac remodeling induced by Ang II. In cardiomyocytes, CYP2J2/EETs protect Ang II induced cardiomyocyte hypertrophy by attenuating oxidative stress-mediated NF-?Bp65 nuclear translocation via PPAR-y activation. Moreover, CYP2J2/EETs inhibit cardiac fibrosis by reducing paracrine manner of cardiomyocytes. In cardiac fibroblasts, CYP2J2/EETs attenuate fibrotic response of cardiac fibroblasts by reducing G?12/13/RhoA/ROCK activity via NO/cGMP pathway activation. In our present study, we illustrated mechanisms involved in Ang-II induced cardiac remodeling and laid theoretical foundation for clinical application of EETs.