C-reactive protein impairs coronary arteriolar dilation to prostacyclin synthase activation: role of peroxynitrite. Academic Article uri icon

abstract

  • 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.

published proceedings

  • J Mol Cell Cardiol

author list (cited authors)

  • Hein, T. W., Qamirani, E., Ren, Y. i., & Kuo, L.

citation count

  • 20

complete list of authors

  • Hein, Travis W||Qamirani, Erion||Ren, Yi||Kuo, Lih

publication date

  • January 2009