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Vascular characterization of mice with endothelial expression of cytochrome P450 4F2
Author(s) -
Cheng Jennifer,
Edin Matthew L.,
Hoopes Samantha L.,
Li Hong,
Bradbury J. Alyce,
Graves Joan P.,
DeGraff Laura M.,
Lih Fred B.,
Garcia Victor,
Shaik Jafar Sadik B.,
Tomer Kenneth B.,
Flake Gordon P.,
Falck John R.,
Lee Craig R.,
Poloyac Samuel M.,
Schwartzman Michal L.,
Zeldin Darryl C.
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-241927
Subject(s) - cytochrome p450 , chemistry , biology , microbiology and biotechnology , cancer research , biochemistry , metabolism
Cytochrome P450 (CYP) 4A and 4F enzymes metabolize arachidonic acid to 20‐hydroxyeico‐satetraenoic acid (20‐HETE). Although CYP4A‐derived 20‐HETE is known to have prohypertensive and proangiogenic properties, the effects of CYP4F‐derived metabolites are not well characterized. To investigate the role of CYP4F2 in vascular disease, we generated mice with endothelial expression of human CYP4F2 (Tie2‐CYP4F2‐Tr). LC/MS/MS analysis revealed 2‐fold increases in 20‐HETE levels in tissues and endothelial cells (ECs), relative to wild‐type (WT) controls. Tie2‐CYP4F2‐Tr ECs demonstrated increases in growth (267.1±33.4 vs . 205.0±13% at 48 h) and tube formation (7.7±1.1 vs . 1.6±0.5 tubes/field) that were 20‐HETE dependent and associated with up‐regulation of prooxidant NADPH oxidase and proangiogenic VEGF. Increases in VEGF and NADPH oxidase levels were abrogated by inhibitors of NADPH oxidase and MAPK, respectively, suggesting the possibility of crosstalk between pathways. Interestingly, IL‐6 levels in Tie2‐CYP4F2‐Tr mice (18.6±2.7 vs . 7.9±2.7 pg/ml) were up‐regulated via NADPH oxidase‐ and 20‐HETE‐dependent mechanisms. Although Tie2‐CYP4F2‐Tr aortas displayed increased vasoconstriction, vasorelaxation and blood pressure were unchanged. Our findings indicate that human CYP4F2 significantly increases 20‐HETE production, CYP4F2‐derived 20‐HETE mediates EC proliferation and angiogenesis via VEGF‐ and NADPH oxidase‐dependent manners, and the Tie2‐CYP4F2‐Tr mouse is a novel model for examining the pathophysiological effects of CYP4F2‐derived 20‐HETE in the vasculature.—Cheng, J., Edin, M. L., Hoopes, S. L., Li, H., Bradbury, J. A., Graves, J. P., DeGraff, L. M., Lih, F. B., Garcia, V., Shaik, J. S. B., Tomer, K. B., Flake, G. P., Falck, J. R., Lee, C. R., Poloyac, S. M., Schwartzman, M. L., Zeldin, D. C. Vascular characterization of mice with endothelial expression of cytochrome P450 4F2. FASEB J . 28, 2915–2931 (2014). www.fasebj.org