CRP as a biomediator of atherosclerosis and its intracellular signaling

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Recently it has become evident that C-reactive protein (CRP) has direct proatherothrombotic effects on vascular cells. We examined the direct effects of CRP on cultured bovine endothelial cells (BAEC) and investigated its underlying signaling.Incubation of BAEC with human recombinant CRP induced a significant increase in PAI-1 expression. Stimulation of BAEC with CRP significantly increased small GTPase RhoA activation. Pretreatment with TAT-C3 (RhoA inhibitor) and Y-27632 (Rho-kinase inhibitor) significantly inhibited CRP-induced PAI-1 expression. NF-_kB activity was markedly enhanced by CRP and pretreatment with Y-27632 inhibited its activation. Parthenolide, SN50 and BAY 11.7082 (NF-_KB inhibitors) significantly blocked CRP-mediated PAI.1 expression. These data suggested that CRP activates Rho/Rho-kinase signaling, which in turn activates NF-_KB activity, resulting in PAI-1 expression in BAEC. These observations provide evidence for the possible involvement of Rho/Rho-kinase signaling in CRP-induced atherothrombogenesis.The expression of PAI.1 was also increased in BAEC by the stimulation with high concentration of glucose (23 mM). Similar to the stimulation with CRP, stimulation with high glucose significantly increased RhoA activation and pretreatment with Y-27632 significantly blocked high glucose-induced PAI-1 expression. NF-_KB activity was also significantly enhanced by high glucose, and pretreatment with Y-27632 inhibited high glucose-induced PAI-1 expression. NF-_KB inhibitors significantly blocked high glucose-mediated PAI-1 expression. These data suggested that high glucose-induced PAI-1 expression in endothelial cells is mediated by NF-_KB activation through the Rho/Rho-kinase pathway. Inhibition of Rho/Rho-kinase signaling might be a novel target for diabetes and metabolic syndrome.