QS152. C-Reactive Protein Induces Endothelial Dysfunction Through Downregulation of eNOS Expression and Increase of Oxidative Stress in PorcinePulmonary Arteries

Abstract

Introduction: C-reactive protein (CRP) is a potent acute phase reactant released in the setting of an inflammatory response. It is also associated with the pathogenesis of vascular disease and potentiates the progression of pulmonary pathology in acute lung injury, sepsis, pulmonary artery hypertension and acute respiratory distress syndrome (ARDS). However, it is unclear whether CRP directly induces endothelial dysfunction in the pulmonary system. The objective of this study was to determine the effect and molecular mechanisms of CRP on endothelial functions in porcine pulmonary arteries (PPA). Methods: PPA 5-mm rings were incubated with increasing concentrations of human CRP (1, 10, and 25 μg/mL). A myograph tension system was utilized to evaluate vasomotor function of the PPA rings. Each PPA group was evaluated for vessel contraction induced by a thromboxane analog (U46619) and vasorelaxation by bradykinin or sodium nitroprusside (SNP). The endothelial nitric oxide synthase (eNOS) expression was measured using real time PCR. Superoxide anion (O−2) production was analyzed by the lucegenin-enhanced chemiluminescence method. Results: In response to 10−6 M bradykinin, endothelium-dependent vasorelaxation of the PPA rings decreased by 25%, and 53% at CRP concentrations of 10 and 25 μg/mL, respectively, compared with untreated controls (P<0.05). CRP did not alter maximum vessel contraction in response to U46619. Endothelium-independent relaxation in response to SNP did not show significant changes between treated and control groups. Expression of eNOS mRNA was reduced by 14% and 58% at CRP concentrations of 10 and 25 μg/mL, respectively, compared with controls in PPA. O−2 production was increased by 70% and 146% in similarly treated PPA rings at equivalent CRP concentrations of 10 and 25 μg (P<0.05). Conclusions: CRP at clinically relevant concentrations impairs endothelium-dependent vasorelaxation in PPA. This endothelial dysfunction is associated with decreased eNOS expression as well as increased free radical production in CRP-treated PPA. These findings suggest that CRP may propagate pulmonary artery endothelial dysfunction during inflammation, thereby contributing to the pulmonary pathology.