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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2088.)
© 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

Tetsuya Nakakuki; Masaaki Ito; Hitoshi Iwasaki; Yasuko Kureishi; Ryuji Okamoto; Nobuyuki Moriki; Mariko Kongo; Shinya Kato; Norikazu Yamada; Naoki Isaka; Takeshi Nakano

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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