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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:534.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Transcriptional Inhibition of Protease-Activated Receptor-1 Expression by Prostacyclin in Human Vascular Smooth Muscle Cells

Robert Pape; Bernhard H. Rauch; Anke C. Rosenkranz; Gernot Kaber; Karsten Schrör

From the Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Germany.

Correspondence to Bernhard H. Rauch, MD, Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Moorenstr. 5, D-40225 Düsseldorf, Germany. E-mail rauchb{at}uni-duesseldorf.de

Abstract

Objective— Stimulation of protease-activated receptor-1 (PAR-1) by thrombin causes vascular smooth muscle cell (SMC) mitogenesis and has been implicated in the vascular response to injury. Vascular injury is also associated with enhanced formation of PGE₂ and PGI₂ (prostacyclin). This study investigates whether PGI₂ and PGE₂ modify the expression of PAR-1 and the cellular response to thrombin in human SMC.

Methods and Results— The PGI₂-mimetic iloprost (1 to 100 nmol/L) attenuated mRNA, total protein, and cell surface expression of PAR-1. This was associated with inhibition of thrombin-induced mitogenesis and migration. Comparable inhibition of PAR-1 expression was observed with the selective IP-receptor agonist cicaprost, the adenylyl cyclase activator forskolin, the phosphodiesterase inhibitor isobutylmethylxanthine and the PKA activator dibutyryl-cAMP. Similar effects of PGE₂ required micromolar concentrations. The specific PKA-inhibitor Myr-PKI prevented PAR-1 downregulation by iloprost. The potential role of Rho family GTPases in PAR-1 regulation was also investigated. Iloprost decreased Rac1 mRNA and the Rac1 inhibitor NSC23766 mimicked the inhibitory effects of iloprost on PAR-1 protein—but not mRNA. The Rho kinase inhibitor Y27632 did not influence PAR-1 expression.

Conclusions— IP-receptor agonists may limit the mitogenic actions of thrombin in human SMC by downregulating PAR-1 via modulation of cAMP-/PKA- and Rac1-dependent signaling pathways.

PAR-1 mediates thrombin-induced mitogenesis in vascular SMCs. This study reports transcriptional downregulation of PAR-1 by the PGI₂ mimetic iloprost at low nanomolar concentrations in human vascular SMCs. This may be relevant for the vascular response to injury in vivo to control thrombin-induced neointima formation.

Key Words: protease-activated receptor-1 (PAR-1) • smooth muscle • thrombin • prostaglandins • Rac1