on February 17, 2005
Published online before print February 17, 2005, doi: 10.1161/01.ATV.0000159890.10526.1e
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Submitted on November 24, 2004
Accepted on February 8, 2005
C-Reactive Protein Inhibits Endothelium-Dependent NO-Mediated Dilation in Coronary Arterioles by Activating p38 Kinase and NAD(P)H Oxidase
Erion Qamirani ;
From the Department of Medical Physiology (E.Q., Y.R., L.K.), Cardiovascular Research Institute, The Texas A&M University System Health Science Center, College Station, Tex; and Scott & White Memorial Hospital (T.W.H.), Department of Surgery, College of Medicine, The Texas A&M University System Health Science Center, Temple, Tex.
* To whom correspondence should be addressed. E-mail: THEIN{at}tamu.edu.
Objective--Elevated levels of C-reactive protein (CRP), a proinflammatory marker, are associated with reduced systemic endothelium-dependent NO-mediated dilation in patients with coronary artery disease; however, the direct effect of CRP on coronary microvascular reactivity remains unknown. Herein, we examined whether CRP can modulate endothelium-dependent NO-mediated dilation of coronary arterioles and whether proinflammatory signaling pathways such as stress-activated protein kinases (p38 and c-Jun N-terminal kinase [JNK]) and oxidative stress are involved in the CRP-mediated effect.
Methods and Results--Porcine coronary arterioles were isolated and pressurized without flow for in vitro study. Intraluminal treatment with a clinically relevant concentration of CRP (7 µg/mL; 1 hour) significantly attenuated the NO release and vasodilation to serotonin. Further incubation with the NO precursor L-arginine (3 mmol/L) partially restored serotonin-induced vasodilation. In the presence of superoxide scavenger TEMPOL, NAD(P)H oxidase inhibitor apocynin, or p38 kinase (an upstream activator of NAD(P)H oxidase) inhibitor SB203850, but not xanthine oxidase inhibitor allopurinol or JNK inhibitor SP600125, the detrimental effect of CRP on serotonin-induced dilation was prevented. Dihydroethidium staining showed that CRP produced SB203850- and TEMPOL-sensitive superoxide production in the arteriolar endothelium. CRP treatment of coronary arterioles significantly increased NAD(P)H oxidase activity.
Conclusions--CRP inhibits endothelium-dependent NO-mediated dilation in coronary arterioles by producing superoxide from NAD(P)H oxidase via p38 kinase activation. By impairing endothelium-dependent NO-mediated vasoreactivity, CRP could facilitate the initiation of numerous cardiovascular diseases.
Key words: C-reactive protein • nitric oxide • free radicals • coronary artery disease
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