Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice
Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice
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DOI：
10.1096/fj.10-171488
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发表时间：
2011-02-01
期刊：
影响因子：
4.8
通讯作者：
Lee, Craig R.
中科院分区：
文献类型：
--
作者：
Deng, Yangmei;Edin, Matthew L.;Lee, Craig R.
细胞色素P-450(CYP)衍生的环氧二十碳三烯酸(EETs)具有较强的体外抗炎作用。然而，CYP介导的EET生物合成增加和可溶性环氧化物水解酶(sEH，EPHX2)介导的EET降解在体内对血管炎症的影响尚未得到严格的研究。因此，我们对内毒素引起的急性血管炎症反应进行了研究，其中转基因小鼠内皮细胞表达了人CYP2J2和CYP2C8环氧合酶，小鼠则靶向阻断了EPHX2。与野生型对照相比，转CYP2J2基因、转CYP2C8基因和转EPHX2(-/-)基因小鼠均能显著降低内毒素诱导的肺组织核因子-kappaB信号、细胞黏附分子、趋化因子和细胞因子的表达以及中性粒细胞的浸润。此外，在原代培养的肺内皮细胞中，细胞黏附分子和趋化因子的表达以及由内毒素诱导的核因子-kappaB的活化和细胞趋化因子的表达被减弱。这种衰减被一种假定的EET受体拮抗剂和CYP环氧合酶抑制剂抑制，直接表明CYP环氧合酶来源的EETs具有观察到的抗炎表型。总而言之，这些数据表明，通过增加内皮EET生物合成或全局减少EET水解率来增强CYP环氧合酶途径，可以在体内减弱依赖于NF-kappa B的血管炎症反应，并可能作为一种可行的抗炎治疗策略。--邓，Y.，Edin，M.L.，Theken，K.N.，Schuck，R.N.，Flake，G.P.，Kannon，M.A.，DeGraff，L.M.，Lih，F.B.，Foley，J.，Bradbury，J.A.，Graves，J.P.，Tomer，K.B.，Falck，J.R.，Zeldin，D.C.，Lee，C.R.内皮CYP环氧合酶的过度表达和可溶性环氧化物水解酶的破坏减轻了小鼠的急性血管炎症反应。FASE B J.25,703-713(2011)。Www.fasebj.org
Cytochrome P-450 (CYP)-derived epoxyeicosatrienoic acids (EETs) possess potent anti-inflammatory effects in vitro. However, the effect of increased CYP-mediated EET biosynthesis and decreased soluble epoxide hydrolase (sEH, Ephx2)-mediated EET hydrolysis on vascular inflammation in vivo has not been rigorously investigated. Consequently, we characterized acute vascular inflammatory responses to endotoxin in transgenic mice with endothelial expression of the human CYP2J2 and CYP2C8 epoxygenases and mice with targeted disruption of Ephx2. Compared to wild-type controls, CYP2J2 transgenic, CYP2C8 transgenic, and Ephx2(-/-) mice each exhibited a significant attenuation of endotoxin-induced activation of nuclear factor (NF)-kappa B signaling, cellular adhesion molecule, chemokine and cytokine expression, and neutrophil infiltration in lung in vivo. Furthermore, attenuation of endotoxin-induced NF-kappa B activation and cellular adhesion molecule and chemokine expression was observed in primary pulmonary endothelial cells isolated from CYP2J2 and CYP2C8 transgenic mice. This attenuation was inhibited by a putative EET receptor antagonist and CYP epoxygenase inhibitor, directly implicating CYP epoxygenase-derived EETs with the observed anti-inflammatory phenotype. Collectively, these data demonstrate that potentiation of the CYP epoxygenase pathway by either increased endothelial EET biosynthesis or globally decreased EET hydrolysis attenuates NF-kappa B-dependent vascular inflammatory responses in vivo and may serve as a viable anti-inflammatory therapeutic strategy.-Deng, Y., Edin, M. L., Theken, K. N., Schuck, R. N., Flake, G. P., Kannon, M. A., DeGraff, L. M., Lih, F. B., Foley, J., Bradbury, J. A., Graves, J. P., Tomer, K. B., Falck, J. R., Zeldin, D. C., Lee, C. R. Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice. FASEB J. 25, 703-713 (2011). www.fasebj.org