C-reactive protein impairs coronary arteriolar dilation to prostacyclin synthase activation: Role of peroxynitrite

Endothelium-derived vasodilators, i.e., nitric oxide (NO), prostacyclin (PGI2) and prostaglandin E2 (PGE2), 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 PGI2 release. PGI2 synthase (PGI2-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 μg/mL, 60 min) attenuated vasodilations to serotonin and AA but not to nitroprusside, exogenous PGI2, or hydrogen peroxide (endothelium-dependent PGE2 activator). CRP also reduced basal NO production, caused tyrosine nitration of endothelial PGI2-S, and inhibited AA-stimulated PGI2 release from arterioles. Peroxynitrite scavenger urate failed to restore serotonin dilation, but preserved AA-stimulated PGI2 release/dilation and prevented PGI2-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 PGI2 synthesis, and thus endothelium-dependent PGI2-mediated dilation, by inhibiting PGI2-S activity through tyrosine nitration. By impairing PGI2-S function, and thus PGI2 release, CRP could promote endothelial dysfunction and participate in the development of coronary artery disease.