Thrombin activates the p21-activated kinase in pulmonary artery smooth muscle cells

Agnes Görlach; Rachida S. BelAiba; John Hess; Thomas Kietzmann

doi:10.1160/TH05-01-0006

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 93(06): 1168-1175
DOI: 10.1160/TH05-01-0006

Cell Signalling and Vessel Remodelling

Schattauer GmbH

Thrombin activates the p21-activated kinase in pulmonary artery smooth muscle cells

Role in tissue factor expression

Agnes Görlach

¹Experimental Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich at the Technical University Munich, Munich, Germany

,

Rachida S. BelAiba

¹Experimental Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich at the Technical University Munich, Munich, Germany

,

John Hess

¹Experimental Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich at the Technical University Munich, Munich, Germany

,

Thomas Kietzmann

²Faculty of Chemistry, Erwin-Schrödinger-Strasse, University of Kaiserslautern, Kaiserslautern, Germany

› Author Affiliations

Abstract

Summary

The p21-activated serine/threonine kinases (PAK) play an important role in a variety of cellular functions. However, their role in the smooth muscle response to thrombin, which is activated upon vascular injury and promotes vascular remodelling processes, is not resolved. Here we investigated the role of PAK in thrombin signalling and regulation of tissue factor (TF), the activator of the extrinsic coagulation cascade, in pulmonary artery smooth muscle cells (PASMC), the main cell type responsible for vascular remodelling in pulmonary hypertension. PAK was rapidly phosphorylated in response to thrombin. Thrombin and active PAKT423E phosphorylated p38 MAP kinase (p38MAPK), ERK1/2, phosphatidylinositol-dependent kinase-1 (PDK1) and protein kinase B/Akt (PKB) whereas kinase-deficient PAK1 prevented activation of these kinases by thrombin. In addition, kinase-deficient MKK3 inhibited activation of PDK1 and PKB by thrombin. Further, thrombin and active PAK1 induced TF expression and promoter activity while kinase-deficient PAK1 diminished thrombin-induced TF upregulation. Moreover, kinase-deficient MKK3, PDK1 and PKB inhibited thrombin- and PAK-dependent TF expression and promoter activity. Together these findings show that PAK is a critical element of thrombin signalling in PASMC which is involved in the regulation of TF expression by sequentially activating MKK3/p38MAPK, PDK1 and PKB. Thus, PAK may play an important role in promoting vascular remodelling processes in pulmonary hypertension.

Keywords

Thrombin - PAK - protein kinase B/Akt - tissue factor - p38 MAP kinase

Full Text

References

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