CYP2C29 produces superoxide in response to shear stress.
OBJECTIVE
Activation of CYP2C29 releases superoxide during shear stress-induced dilation (SSID).


METHODS
Mesenteric arteries isolated from female eNOS-KO and WT mice were cannulated and pressurized. Vasodilation and superoxide production in response to shear stress were assessed.


RESULTS
Shear stress-induced dilation was significantly attenuated in vessels of eNOS-KO compared with WT mice, which was normalized by tempol and PEG-Catalase, in a PPOH (inhibitor of CYP2C29)-sensitive manner, but remained unaffected by VAS2870 and allopurinol, inhibitors of NADPH oxidase and xanthine oxidase, respectively. NaNO(2)-induced dilation was comparable in both strains of mice. Confocal microscopy shows that SS-stimulated superoxide was increased particularly in the endothelium of eNOS-KO mice. HPLC analysis of 2-EOH indicated an increase in SS-stimulated superoxide in vessels of eNOS-KO mice, a response that was sensitive to PPOH. Inhibition of soluble epoxide hydrolase significantly enhanced SSID without affecting SS-stimulated superoxide production. CYP2C29 and catalase were upregulated, and exogenous H(2)O(2) caused vasoconstriction in vessels of eNOS-KO mice.


CONCLUSIONS
CYP2C29 synthesizes EETs to mediate SSID, and simultaneously releases superoxide and sequential H(2)O(2), which in turn impair SSID.
Department of Physiology, New York Medical College, Valhalla, New York 10595, USA. dong_sun@nymc.edu
Dong
D
Sun
Caroline
C
Ojaimi
Hongyan
H
Wu
Gabor
G
Kaley
An
A
Huang
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001583:Benzoxazoles / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006861:Hydrogen Peroxide / Q000378:metabolism; D008638:Mesenteric Arteries / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D011092:Polyethylene Glycols / Q000494:pharmacology; D013113:Spin Labels; D013312:Stress, Physiological; D013481:Superoxides / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014664:Vasodilation
C511179:3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo(4,5-d)pyrimidine; D000975:Antioxidants; D001583:Benzoxazoles; D003497:Cyclic N-Oxides; D013113:Spin Labels; D014230:Triazoles; C070295:catalase-polyethylene glycol; D013481:Superoxides; D011092:Polyethylene Glycols; D003577:Cytochrome P-450 Enzyme System; D006861:Hydrogen Peroxide; D002374:Catalase; C086292:Cyp2c29 protein, mouse; D000072467:Cytochrome P450 Family 2; C001803:tempol