CYP 2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPK α2 and enhancing nuclear translocation of Akt1

Abstract

SummaryCytochrome P450 epoyxgenase 2J2 and epoxyeicosatrienoic acids (EETs) are known to protect against cardiac hypertrophy and heart failure, which involve the activation of 5′‐AMP‐activated protein kinase (AMPK) and Akt. Although the functional roles of AMPK and Akt are well established, the significance of cross talk between them in the development of cardiac hypertrophy and antihypertrophy of CYP2J2 and EETs remains unclear. We investigated whether CYP2J2 and its metabolites EETs protected against cardiac hypertrophy by activating AMPKα2 and Akt1. Moreover, we tested whether EETs enhanced cross talk between AMPKα2 and phosphorylated Akt1 (p‐Akt1), and stimulated nuclear translocation of p‐Akt1, to exert their antihypertrophic effects. AMPKα2−/− mice that overexpressed CYP2J2 in heart were treated with Ang II for 2 weeks. Interestingly, overexpression of CYP2J2 suppressed cardiac hypertrophy and increased levels of atrial natriuretic peptide (ANP) in the heart tissue and plasma of wild‐type mice but not AMPKα2−/− mice. The CYP2J2 metabolites, 11,12‐EET, activated AMPKα2 to induce nuclear translocation of p‐Akt1 selectively, which increased the production of ANP and therefore inhibited the development of cardiac hypertrophy. Furthermore, by co‐immunoprecipitation analysis, we found that AMPKα2β2γ1 and p‐Akt1 interact through the direct binding of the AMPKγ1 subunit to the Akt1 protein kinase domain. This interaction was enhanced by 11,12‐EET. Our studies reveal a novel mechanism in which CYP2J2 and EETs enhanced Akt1 nuclear translocation through interaction with AMPKα2β2γ1 and protect against cardiac hypertrophy and suggest that overexpression of CYP2J2 might have clinical potential to suppress cardiac hypertrophy and heart failure.

Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria

“…CYP-mediated AMPKα inhibition could provide a novel mechanism through which CYPs activate mTOR and function as a “brake” on cellular catabolism. In breast cancer, EETs appear to be acting in the opposite direction compared to cardiac myocytes, where they activate AMPKα2 (Wang et al, 2016). In cardiac myocytes, EETs improve viability and colony formation through activation of autophagy and respiration (Samokhvalov et al, 2013).…”

CYP2J2 metabolites, epoxyeicosatrienoic acids, attenuate Ang II-induced cardiac fibrotic response by targeting Gα12/13

“…Furthermore, other research was performed illustrating that EETs could inhibit oxidative stress by activating PPAR- (13). Interestingly, we have found that CYP2J2 and EETs enhanced Akt1 nuclear translocation through interaction with AMPK221 and protected against cardiac hypertrophy (14). As cellular cross-talk contributes largely to cardiac remodeling, we studied the effects and mechanisms of EETs on cross-talk between cardiomyocytes, cardiac fibroblasts, and macrophages.…”

“…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-/oxidative stress/SERCA2a/ER stress pathway and interaction of Akt1 and AMPK221 (8,13,14). Moreover, EETs attenuate pro-fibrotic and pro-inflammatory responses of cardiomyocytes transmitted to cardiac fibroblasts and macrophages, respectively (13,15).…”

“…metabolic pathway to cardiovascular diseases, given the impact of EETs to cardiovascular physiology (6)(7)(8)(9)(10). Our previous works have demonstrated protective effects of the AA-CYP2J2-EET metabolic pathway from the perspective of cardiomyocytes and cellular cross-talk (8,(13)(14)(15). However, the role of the AA-CYP2J2-EET system on cardiac fibrosis and fibroblasts has not been completely elucidated.…”

Inhibition of soluble epoxide hydrolase attenuates a high-fat diet-mediated renal injury by activating PAX2 and AMPK

“…Recently, AMPK was reported to be activated by cytochrome P450 (CYP) 2J2 and its metabolites, such as epoxyeicosatrienoic acids (EETs), which contribute to the attenuation of cardiac injuries (31)(32)(33). EETs are not only the metabolites of arachidonic acid (ARA) mediated by CYP2C and CYP2J, but also the substrates for the enzyme soluble epoxide hydrolase (sEH, encoded by EPHX2) (34,35).…”