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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

Christine Veith
1   Universities 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
2   Department of Biochemistry, Justus-Liebig-University, Giessen, Germany, member of the DZL, Excellence Cluster Cardio-Pulmonary System (ECCPS)
,
Bhola Kumar Dahal
1   Universities 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
3   Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
,
Kirsten Murmann
1   Universities 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
2   Department of Biochemistry, Justus-Liebig-University, Giessen, Germany, member of the DZL, Excellence Cluster Cardio-Pulmonary System (ECCPS)
,
Werner Seeger
1   Universities 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
1   Universities 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
1   Universities 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
3   Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
› Author Affiliations Financial support: Deutsche Forschungsgemeinschaft (WE 1978/4–1; SFB-TR 84); Excellence Cluster Cardio-Pulmonary System; EU FP6 “PULMOTENSION” (LSHM-CT-2005–018725); Graduate scholarship of the Justus-Liebig-University Giessen, Germany.
Further Information

Publication History

Received: 18 December 2013

Accepted after major revision: 10 July 2014

Publication Date:
18 November 2017 (online)

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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

 

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