title: Cytochrome P-450 epoxygenases protect endothelial cells from apoptosis induced by tumor necrosis factor-alpha via MAPK and PI3K/Akt signaling pathways.
abstract: Endothelial cells play a vital role in the maintenance of cardiovascular homeostasis. Epoxyeicosatrienoic acids (EETs), cytochrome P-450 (CYP) epoxygenase metabolites of arachidonic acid in endothelial cells, possess potent and diverse biological effects within the vasculature. We evaluated the effects of overexpression of CYP epoxygenases on tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis in bovine aortic endothelial cells. CYP epoxygenase overexpression significantly increased endothelial cell viability and inhibited TNF-alpha induction of endothelial cell apoptosis as evaluated by morphological analysis of nuclear condensation, DNA laddering, and fluorescent-activated cell sorting (FACS) analysis. CYP epoxygenase overexpression also significantly inhibited caspase-3 activity and downregulation of Bcl-2 expression induced by TNF-alpha. The antiapoptotic effects of CYP epoxygenase overexpression were significantly attenuated by inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK signaling pathways; however, inhibition of endothelial nitric oxide synthase activity had no effect. Furthermore, CYP epoxygenase overexpression significantly attenuated the extent of TNF-alpha-induced ERK1/2 dephosphorylation in a time-dependent manner and significantly increased PI3K expression and Akt phosphorylation in both the presence and absence of TNF-alpha. Collectively, these results suggest that CYP epoxygenase overexpression, which is known to increase EET biosynthesis, significantly protects endothelial cells from apoptosis induced by TNF-alpha. This effect is mediated, at least in part, through inhibition of ERK dephosphorylation and activation of PI3K/Akt signaling.
authors.affiliation: Institite of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, #1095 Jie Fang Da Dao Avenue, Wuhan 430030, People's Republic of China.
authors.forename: Shilin
authors.initials: S
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Ji-Xiong
authors.initials: JX
authors.lastname: Chen
authors.forename: Craig R
authors.initials: CR
authors.lastname: Lee
authors.forename: John M
authors.initials: JM
authors.lastname: Seubert
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Zhong-Ren
authors.initials: ZR
authors.lastname: Chao
authors.forename: De-Ding
authors.initials: DD
authors.lastname: Tao
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Gong
authors.forename: Zai-Ying
authors.initials: ZY
authors.lastname: Lu
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002417:Cattle; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D003577:Cytochrome P-450 Enzyme System; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases