CYP2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPKα2 and enhancing nuclear translocation of Akt1.
CYP2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPKα2 and enhancing nuclear translocation of Akt1.
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CYP2J2 及其代谢物（环氧二十碳三烯酸）通过激活 AMPK2 和增强 Akt1 的核转位来减轻心脏肥大
DOI：
10.1111/acel.12507
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发表时间：
2016-10
期刊：
影响因子：
7.8
通讯作者：
Wang DW
中科院分区：
文献类型：
--
作者：
Wang B;Zeng H;Wen Z;Chen C;Wang DW
已知细胞色素P450环氧合酶2 J2和环氧二十碳三烯酸（ESTs）可防止心脏肥大和心力衰竭，这涉及5′-AMP-活化蛋白激酶（AMPK）和Akt的活化。虽然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肌肥厚的发展中的意义以及CYP 2 J2和Ekaryotic的抗肥厚作用仍不清楚。我们研究了CYP 2 J2及其代谢产物雌二醇是否通过激活AMPKα2和Akt 1来保护心肌肥大。此外，我们还检测了雌二醇是否增强AMPKα2和磷酸化Akt 1（p-Akt 1）之间的串扰，并刺激p-Akt 1的核转位，以发挥其抗肥大作用。心脏中过表达CYP 2 J2的AMPKα2−/−小鼠用Ang II治疗2周。有趣的是，CYP 2 J2的过表达抑制了野生型小鼠心脏组织和血浆中的心脏肥大和心钠素（ANP）水平升高，但AMPKα2−/−小鼠没有。CYP 2 J2代谢产物11，12-EET激活AMPKα2，选择性诱导p-Akt 1核转位，增加ANP的产生，从而抑制心肌肥大的发展。此外，通过免疫共沉淀分析，我们发现AMPKα2β2γ1和p-Akt 1通过AMPKγ1亚基与Akt 1蛋白激酶结构域的直接结合而相互作用。11，12-EET增强了这种相互作用。我们的研究揭示了一种新的机制，其中CYP 2 J2和Eketamine通过与AMPKα2β2γ1相互作用增强Akt 1核转位并保护心肌肥厚，并表明CYP 2 J2的过表达可能具有抑制心肌肥厚和心力衰竭的临床潜力。
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.
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DOI：
10.1046/j.1432-1327.1999.00774.x
发表时间：
1999-10-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Masure, S;Haefner, B;Richardson, A
通讯作者：
Richardson, A
影响因子：
120.7
作者：
Redfield, MM;Jacobsen, SJ;Rodeheffer, RJ
通讯作者：
Rodeheffer, RJ
影响因子：
10.8
作者：
Guo, Rui;Ren, Jun
通讯作者：
Ren, Jun
DOI：
10.1073/pnas.1103300108
发表时间：
2011-11-08
影响因子：
11.1
作者：
Klaiber, Michael;Dankworth, Beatrice;Kuhn, Michaela
通讯作者：
Kuhn, Michaela
影响因子：
4.8
作者：
Andjelkovic, M;Alessi, DR;Hemmings, BA
通讯作者：
Hemmings, BA