Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice.
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)-κB signaling, cellular adhesion molecule, chemokine and cytokine expression, and neutrophil infiltration in lung in vivo. Furthermore, attenuation of endotoxin-induced NF-κB 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-κB-dependent vascular inflammatory responses in vivo and may serve as a viable anti-inflammatory therapeutic strategy.
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599-7569, USA.
Yangmei
Y
Deng
Matthew L
ML
Edin
Katherine N
KN
Theken
Robert N
RN
Schuck
Gordon P
GP
Flake
M Alison
MA
Kannon
Laura M
LM
DeGraff
Fred B
FB
Lih
Julie
J
Foley
J Alyce
JA
Bradbury
Joan P
JP
Graves
Kenneth B
KB
Tomer
John R
JR
Falck
Darryl C
DC
Zeldin
Craig R
CR
Lee
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D065727:Cytochrome P-450 CYP2C8; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000502:physiology; D019446:Endotoxemia / Q000139:chemically induced; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000201:enzymology*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014652:Vascular Diseases / Q000201:enzymology*
C000717350:CYP2J2 protein, human; D008070:Lipopolysaccharides; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D000090762:Cytochrome P-450 CYP2J2; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse