C‐reactive protein inhibits endothelium‐dependent prostacyclin synthase‐mediated dilation of coronary arterioles: role of peroxynitrite

Abstract

We have recently shown that C-reactive protein (CRP), a biomarker of cardiovascular disease, inhibits nitric oxide (NO)-mediated vasodilation via NAD(P)H oxidase-dependent superoxide (O2−) production. Here, we examined whether CRP can influence the response to another endothelium-derived vasodilator – prostacyclin (PGI2). Porcine coronary arterioles were isolated and pressurized without flow for in vitro study. Endothelium-dependent agonist arachidonic acid (AA) stimulated PGI2 release and dilation. PGI2 synthase (PGI2S) inhibitor trans-2-phenyl cyclopropylamine blocked dilation to AA but not to endothelium-dependent NO-mediated agonist serotonin. Luminal administration of CRP (pathophysiologic level of 7 μg/ml, 60 min) attenuated dilations to serotonin and AA but not to exogenous PGI2. CRP also reduced basal NO level, caused tyrosine nitration of PGI2S, and inhibited PGI2 release. Peroxynitrite scavenger urate prevented inhibitory actions of CRP on PGI2S and PGI2 release/dilation but not on serotonin-induced dilation. Moreover, NO synthase inhibitor L-NAME or O2− scavenger TEMPOL prevented the detrimental effect of CRP on AA-induced dilation. Our data show that CRP inhibits endothelium-dependent PGI2S-mediated dilation of coronary arterioles. This vascular dysfunction is a result of PGI2S nitration by peroxynitrite derived from basal NO and CRP-induced O2− production. (HL-71761 to LK)