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

Hein, Travis W.; Qamirani, Erion; Ren, Yi; Kuo, Lih

doi:10.1016/j.yjmcc.2009.04.015

« Previous Next »Journal of Molecular and Cellular Cardiology
Volume 47, Issue 2 , Pages 196-202, August 2009

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

Travis W. Hein
- 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
- Corresponding author. Tel.: +1 254 724 3550; fax: +1 254 742 7181.
- These authors contributed equally to this work.
Erion Qamirani
- Department of Systems Biology and Translational Medicine, Cardiovascular Research Institute, College of Medicine, Texas A&M Health Science Center, Temple, TX 76504, USA
- These authors contributed equally to this work.
Yi Ren
- Department of Systems Biology and Translational Medicine, Cardiovascular Research Institute, College of Medicine, Texas A&M Health Science Center, Temple, TX 76504, USA
Lih Kuo
- 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
- Department of Systems Biology and Translational Medicine, Cardiovascular Research Institute, College of Medicine, Texas A&M Health Science Center, Temple, TX 76504, USA

Received 5 March 2009; received in revised form 23 April 2009; accepted 24 April 2009. published online 04 May 2009.

Abstract

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.