C-reactive protein impairs coronary arteriolar dilation to prostacyclin synthase activation: role of peroxynitrite.
Endothelium-derived vasodilators, i.e., nitric oxide (NO), prostacyclin (PGI(2)) and prostaglandin E(2) (PGE(2)), play important roles in maintaining cardiovascular homeostasis. C-reactive protein (CRP), a biomarker of inflammation and cardiovascular disease, has been shown to inhibit NO-mediated vasodilation. The goal of this study was to determine whether CRP also affects endothelial arachidonic acid (AA)-prostanoid pathways for vasomotor regulation. Porcine coronary arterioles were isolated and pressurized for vasomotor study, as well as for molecular and biochemical analysis. AA elicited endothelium-dependent vasodilation and PGI(2) release. PGI(2) synthase (PGI(2)-S) inhibitor trans-2-phenyl cyclopropylamine blocked vasodilation to AA but not to serotonin (endothelium-dependent NO-mediated vasodilator). Intraluminal administration of a pathophysiological level of CRP (7 microg/mL, 60 min) attenuated vasodilations to serotonin and AA but not to nitroprusside, exogenous PGI(2), or hydrogen peroxide (endothelium-dependent PGE(2) activator). CRP also reduced basal NO production, caused tyrosine nitration of endothelial PGI(2)-S, and inhibited AA-stimulated PGI(2) release from arterioles. Peroxynitrite scavenger urate failed to restore serotonin dilation, but preserved AA-stimulated PGI(2) release/dilation and prevented PGI(2)-S nitration. NO synthase inhibitor L-NAME and superoxide scavenger TEMPOL also protected AA-induced vasodilation. Collectively, our results suggest that CRP stimulates superoxide production and the subsequent formation of peroxynitrite from basal released NO compromises PGI(2) synthesis, and thus endothelium-dependent PGI(2)-mediated dilation, by inhibiting PGI(2)-S activity through tyrosine nitration. By impairing PGI(2)-S function, and thus PGI(2) release, CRP could promote endothelial dysfunction and participate in the development of coronary artery disease.
Scott and White Memorial Hospital, Department of Surgery, College of Medicine, Texas A&M Health Science Center, 702 Southwest H.K. Dodgen Loop, Temple, TX 76504, USA. THEIN@tamu.edu
Travis W
TW
Hein
Erion
E
Qamirani
Yi
Y
Ren
Lih
L
Kuo
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001160:Arterioles / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D002097:C-Reactive Protein / Q000378:metabolism*; D002469:Cell Separation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D011464:Epoprostenol / Q000096:biosynthesis; D007150:Immunohistochemistry; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D034421:Sus scrofa; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014666:Vasomotor System / Q000187:drug effects
D030421:Peroxynitrous Acid; D009599:Nitroprusside; D016718:Arachidonic Acid; D009569:Nitric Oxide; D012701:Serotonin; C002744:3-nitrotyrosine; D014443:Tyrosine; D002097:C-Reactive Protein; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase