Endothelial nitric oxide synthase-dependent tyrosine nitration of prostacyclin synthase in diabetes in vivo.
There is evidence that reactive nitrogen species are implicated in diabetic vascular complications, but their sources and targets remain largely unidentified. In the present study, we aimed to study the roles of endothelial nitric oxide synthase (eNOS) in diabetes. Exposure of isolated bovine coronary arteries to high glucose (30 mmol/l d-glucose) but not to osmotic control mannitol (30 mmol/l) switched angiotensin II-stimulated prostacyclin (PGI(2))-dependent relaxation into a persistent vasoconstriction that was sensitive to either indomethacin, a cyclooxygenase inhibitor, or SQ29548, a selective thromboxane receptor antagonist. In parallel, high glucose, but not mannitol, significantly increased superoxide and 3-nitrotyrosine in PGI(2) synthase (PGIS). Concurrent administration of polyethylene-glycolated superoxide dismutase (SOD), l-nitroarginine methyl ester, or sepiapterin not only reversed the effects of high glucose on both angiotensin II-induced relaxation and PGI(2) release but also abolished high-glucose-enhanced PGIS nitration, as well as its association with eNOS. Furthermore, diabetes significantly suppressed PGIS activity in parallel with increased superoxide and PGIS nitration in the aortas of diabetic C57BL6 mice but had less effect in diabetic mice either lacking eNOS or overexpressing human SOD (hSOD(+/+)), suggesting an eNOS-dependent PGIS nitration in vivo. We conclude that diabetes increases PGIS nitration in vivo, likely via dysfunctional eNOS.
Nie
Hong
H
BSEB 325, Section of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA.
Wu
Ji-Liang
JL
Zhang
Miao
M
Xu
Jian
J
Zou
Ming-Hui
MH
D000818:Animals; D001011:Aorta / Q000503:physiopathology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000201:enzymology*; D011464:Epoprostenol / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D026361:Reactive Nitrogen Species / Q000502:physiology; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects
D026361:Reactive Nitrogen Species; D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase