Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein

<jats:p> <jats:bold> <jats:italic> <jats:bold> <jats:italic>Background</jats:italic> </jats:bold> — </jats:italic> </jats:bold> C-reactive protein (CRP) has been suggested to actively participate in the development of atherosclerosis. In the present study, we examined the role of the potent endothelium-derived vasoactive factor endothelin-1 (ET-1) and the inflammatory cytokine interleukin-6 (IL-6) as mediators of CRP-induced proatherogenic processes. </jats:p> <jats:p> <jats:bold> <jats:italic> <jats:bold> <jats:italic>Methods and Results</jats:italic> </jats:bold> — </jats:italic> </jats:bold> Saphenous vein endothelial cells (HSVECs) were incubated with human recombinant CRP (25 μg/mL, 24 hours) and the expression of vascular cell adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM-1), and monocyte chemoattractant chemokine-1 was determined. The effects of CRP on LDL uptake were assessed in macrophages using immunofluorescent labeling of CD32 and CD14. In each study, the effect of endothelin antagonism (bosentan) and IL-6 inhibition (monoclonal anti-IL-6 antibodies) was examined. The effects of CRP on the secretion of ET-1 and IL-6 from HSVECs were also evaluated. Incubation of HSVECs with recombinant human CRP resulted in a marked increase in ICAM-1 and VCAM-1 expression ( <jats:italic>P</jats:italic> <0.001). Likewise, CRP caused a significant increase in monocyte chemoattractant chemokine-1 production, a key mediator of leukocyte transmigration ( <jats:italic>P</jats:italic> <0.001). CRP caused a marked and sustained increase in native LDL uptake by macrophages ( <jats:italic>P</jats:italic> <0.05). These proatherosclerotic effects of CRP were mediated, in part, via increased secretion of ET-1 and IL-6 ( <jats:italic>P</jats:italic> <0.01) and were attenuated by both bosentan and IL-6 antagonism ( <jats:italic>P</jats:italic> <0.01). </jats:p> <jats:p> <jats:bold> <jats:italic> <jats:bold> <jats:italic>Conclusions</jats:italic> </jats:bold> — </jats:italic> </jats:bold> CRP actively promotes a proatherosclerotic and proinflammatory phenotype. These effects are mediated, in part, via the production of ET-1 and IL-6 and are attenuated by mixed ET <jats:sub>A/B</jats:sub> receptor antagonism and IL-6 inhibition. Bosentan may be useful in decreasing CRP-mediated vascular disease. </jats:p>