Hypoxia- or PDGF-BB-dependent paxillin tyrosine phosphorylation in pulmonary hypertension is reversed by HIF-1α depletion or imatinib treatment

Christine Veith; Dariusz Zakrzewicz; Bhola Kumar Dahal; Zoltán Bálint; Kirsten Murmann; Malgorzata Wygrecka; Werner Seeger; Ralph Theo Schermuly; Norbert Weissmann; Grazyna Kwapiszewska

doi:10.1160/th13-12-1031

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 112(06): 1288-1303
DOI: 10.1160/th13-12-1031

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Hypoxia- or PDGF-BB-dependent paxillin tyrosine phosphorylation in pulmonary hypertension is reversed by HIF-1α depletion or imatinib treatment

Authors

Christine Veith

¹Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany
Dariusz Zakrzewicz

²Department of Biochemistry, Justus-Liebig-University, Giessen, Germany, member of the DZL, Excellence Cluster Cardio-Pulmonary System (ECCPS)
Bhola Kumar Dahal

¹Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany
Zoltán Bálint

³Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
Kirsten Murmann

¹Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany
Malgorzata Wygrecka

²Department of Biochemistry, Justus-Liebig-University, Giessen, Germany, member of the DZL, Excellence Cluster Cardio-Pulmonary System (ECCPS)
Werner Seeger

¹Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany
Ralph Theo Schermuly

¹Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany
Norbert Weissmann

¹Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany
Grazyna Kwapiszewska

³Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria

Abstract

Summary

Chronic exposure to hypoxia induces a pronounced remodelling of the pulmonary vasculature leading to pulmonary hypertension (PH). The remodelling process also entails increased proliferation and decreased apoptosis of pulmonary arterial smooth muscle cells (PASMC), processes regulated by the cytoskeletal protein paxillin. In this study, we aimed to examine the molecular mechanisms leading to deregulation of paxillin in PH. We detected a time-dependent increase in paxillin tyrosine 31 (Y31) and 118 (Y118) phosphorylation following hypoxic exposure (1 % O₂) or platelet-derived growth factor (PDGF)-BB stimulation of primary human PASMC. In addition, both, hypoxia- and PDGF-BB increased the nuclear localisation of phospho-paxillin Y31 as indicated by immunofluorescence staining in human PASMC. Elevated paxillin tyrosine phosphorylation in human PASMC was attenuated by hypoxia-inducible factor (HIF)-1α depletion or by treatment with the PDGF-BB receptor antagonist, imatinib. Moreover, we observed elevated paxillin Y31 and Y118 phosphorylation in the pulmonary vasculature of chronic hypoxic mice (21 days, 10 % O₂) which was reversible by imatinib-treatment. PDGF-BB-dependent PASMC proliferation was regulated via the paxillin-Erk1/2-cyclin D1 pathway. In conclusion, we suggest paxillin up-regulation and phosphorylation as an important mechanism of vascular remodelling underlying pulmonary hypertension.

Note: Parts of the doctoral thesis of Christine Veith are integrated into this report.

Keywords

Pulmonary arterial smooth muscle cells - cytoskeletal proteins - pulmonary hypertension - pulmonary vascular remodelling

Full Text

References

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