Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice

被引:112
作者
Deng, Yangmei [1 ]
Edin, Matthew L. [2 ]
Theken, Katherine N. [1 ]
Schuck, Robert N. [1 ]
Flake, Gordon P. [2 ]
Kannon, M. Alison [1 ]
DeGraff, Laura M. [2 ]
Lih, Fred B. [2 ]
Foley, Julie [2 ]
Bradbury, J. Alyce [2 ]
Graves, Joan P. [2 ]
Tomer, Kenneth B. [2 ]
Falck, John R. [3 ]
Zeldin, Darryl C. [2 ]
Lee, Craig R. [1 ]
机构
[1] UNC, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC 27599 USA
[2] Natl Inst Environm Hlth Sci, Natl Inst Hlth, Div Intramural Res, Res Triangle Pk, NC USA
[3] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA
关键词
CYP2J2; CYP2C8; EPHX2; EETs; eicosanoids; inflammation; NF-KAPPA-B; ACUTE LUNG INJURY; ACUTE PSEUDOMONAS PNEUMONIA; BLOOD-PRESSURE REGULATION; ARACHIDONIC-ACID; CYTOCHROME-P450; EPOXYGENASES; CORONARY-ARTERIES; EPOXYEICOSATRIENOIC ACIDS; THERAPEUTIC TARGET; MOLECULAR-CLONING;
D O I
10.1096/fj.10-171488
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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
引用
收藏
页码:703 / 713
页数:11
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