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

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 NOmediated 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 (endotheliumdependent NO-mediated vasodilator). Intraluminal administration of a pathophysiological level of CRP (7 μg/mL, 60 minutes) 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.

Endothelin-1 impairs coronary arteriolar dilation: Role of p38 kinase-mediated superoxide production from NADPH oxidase

“…The released superoxide, following ET-1 stimulation, can be converted to H 2 O 2 by superoxide dismutase or to peroxynitrite after reaction with NO. Since both H 2 O 2 and peroxynitrite have been shown to impair endothelium-dependent NO-mediated vasodilation in coronary arterioles [29, 51], the observed adverse effect of ET-1 in the present study might be the consequence of the formation of H 2 O 2 and/or peroxynitrite. However, administration of reported effective concentrations of scavengers for H 2 O 2 (i.e., catalase) [51] and peroxynitrite (i.e., urate) [29] did not protect the vessels from ET-1 insult (Fig.…”

“…To examine whether the effect of ET-1 is affected by the inhibition of NO synthase (NOS), the vasodilations to serotonin and adenosine were examined in the presence of ET-1 and NOS inhibitor L-NAME (10 μmol/L) [24]. The involvements of superoxide, hydrogen peroxide (H 2 O 2 ) and peroxynitrite in the adverse effect of ET-1 were also examined by co-incubating the vessels with ET-1 plus superoxide scavengers Tempol (1 mmol/L) [28, 29] or MnTBAP (10 μmol/L) [30], H 2 O 2 scavenger catalase (1,000 units/mL) [31], and peroxynitrite scavenger urate (0.1 mmol/L) [29] for 60 minutes, respectively. To determine the contribution of superoxide generation enzyme NADPH oxidase (NOX) in mediating the ET-1 effect, vasodilations to serotonin and adenosine were studied in separate groups of vessels treated with ET-1 (0.1 nmol/L) in combination with NOX inhibitor apocynin (100 μmol/L) [28], VAS2870 (10 μmol/L) [32], NOX2-based assembly inhibitor gp91 ds-tat (10 μmol/L) [33] or Rac1/NOX2 inhibitor mycophenolic acid (10 μmol/L, Santa Cruz Biotechnology) [34].…”

Clinical significance and determinants of prompt recruitment collaterals during primary percutaneous coronary intervention

“…Increased hs-CRP levels resulted in impaired endothelial function and lead to decrease in expression of endothelial-mediated NO and prostacyclin [24]. In addition, previous evidence suggests that NO has a positive modulation over both angiogenesis and arteriogenesis, which are the main contributors of coronary collateral circulation (CCC) development [10,11].…”

The relationship between gamma-glutamyltransferase and coronary collateral circulation in patients with chronic total occlusion

“…The underlying mechanism of this relation with long-term prognosis is unclear but endothelial dysfunction is the implied mechanism. Elevated hs-CRP levels lead to reduction of endothelial production of NO and prostacyclin, up-regulation of endothelial adhesion molecules, generation of superoxide in vascular cells, all of which elicit endothelial dysfunction (45). Previously, a study has demonstrated that high levels of hs-CRP are correlated with poor collateral circulation (46).…”