Wang Bei, Zeng Hesong, Wen Zheng, Chen Chen, Wang Dao Wen
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Aging Cell. 2016 Oct;15(5):940-52. doi: 10.1111/acel.12507. Epub 2016 Jul 14.
Cytochrome 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.
细胞色素P450环氧合酶2J2和环氧二十碳三烯酸（EETs）已知可预防心脏肥大和心力衰竭，这涉及5'-AMP激活蛋白激酶（AMPK）和Akt的激活。尽管AMPK和Akt的功能作用已得到充分证实，但它们之间的相互作用在心脏肥大发展以及CYP2J2和EETs的抗肥大作用中的意义仍不清楚。我们研究了CYP2J2及其代谢产物EETs是否通过激活AMPKα2和Akt1来预防心脏肥大。此外，我们测试了EETs是否增强了AMPKα2与磷酸化Akt1（p-Akt1）之间的相互作用，并刺激p-Akt1的核转位，以发挥其抗肥大作用。对心脏中过表达CYP2J2的AMPKα2（-/-）小鼠用血管紧张素II处理2周。有趣的是，CYP2J2的过表达抑制了野生型小鼠而非AMPKα2（-/-）小鼠的心脏肥大，并增加了心脏组织和血浆中的心钠素（ANP）水平。CYP2J2代谢产物11,12-EET激活AMPKα2以选择性诱导p-Akt1的核转位，这增加了ANP的产生，从而抑制了心脏肥大的发展。此外，通过免疫共沉淀分析，我们发现AMPKα2β2γ1和p-Akt1通过AMPKγ1亚基与Akt1蛋白激酶结构域的直接结合相互作用。这种相互作用被11,12-EET增强。我们的研究揭示了一种新机制，即CYP2J2和EETs通过与AMPKα2β2γ1相互作用增强Akt1核转位并预防心脏肥大，并表明CYP2J2的过表达可能具有抑制心脏肥大和心力衰竭的临床潜力。
