Published online before print August 25, 2005, doi: 10.1161/01.ATV.0000183607.50230.9f
© 2005 American Heart Association, Inc.
Vascular Biology |
Rho/Rho-Kinase Pathway Contributes to C-Reactive Protein–Induced Plasminogen Activator Inhibitor-1 Expression in Endothelial Cells
From the Department of Cardiology, Mie University Graduate School of Medicine, Tsu, Japan.
Correspondence to Masaaki Ito, MD, Department of Cardiology, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie 514-8507, Japan. E-mail mitoka{at}clin.medic.mie-u.ac.jp
Objective— Rho/Rho-kinase pathway plays pivotal roles in cardiovascular diseases including arteriosclerosis and hypertension. Recently it has become evident that C-reactive protein (CRP), a powerful marker for cardiovascular events, has direct proatherothrombotic effects on vascular cells. However, its molecular mechanism has not been fully investigated. We examined the involvement of Rho/Rho-kinase signaling in CRP-induced plasminogen activator inhibitor-1 (PAI-1) expression in bovine aortic endothelial cells (BAECs).
Methods and Results— PAI-1 expression was determined by Western blotting. RhoA activation was determined by an affinity pull-down assay using Rho-binding fragment of rhotekin. NF-
B activity was determined using the luciferase reporter gene. Incubation of BAECs with human recombinant CRP (
25 µg/mL) induced a significant increase in PAI-1 expression. Stimulation of BAECs with CRP significantly increased RhoA activation. Pretreatment with TAT-C3 (a membrane-permeable RhoA inhibitor) and Y-27632 (Rho-kinase inhibitor) significantly inhibited CRP-induced PAI-1 expression. NF-B activity was markedly enhanced by CRP and pretreatment with Y-27632 inhibited its activation. Parthenolide, SN50, and BAY 11-7082 (NF-B inhibitors) significantly blocked CRP-mediated PAI-1 expression.
Conclusions— These data suggested that CRP activates Rho/Rho-kinase signaling, which in turn activates NF-B 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.
Key Words: C-reactive protein • endothelial cells • NF-B • PAI-1 • Rho/Rho-kinase
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