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Acta Physiologica 2009; Volume 195, Supplement 669
The 88th Annual Meeting of The German Physiological Society
3/22/2009-3/25/2009
Giessen, Germany
THE CYTOSKELETAL PROTEIN PAXILLIN IS ASSOCIATED WITH PULMONARY VASCULAR REMODELING
Abstract number: P394
Veith1 C., Weissmann1 N., Seeger1 W., Kwapiszewska1 G.
1University of Giessen Lung Center (UGLC), Department of Internal Medicine II, Klinikstr. 36, 35392 Giessen, Germany, Giessen
Pulmonary arterial hypertension (PAH) is a progressive disease of multifactorial etiology, which has poor prognosis. Idiopathic PAH (iPAH) is one form of pulmonary hypertension and characterized by pronounced vascular remodelling, which leads to a progressive increase in pulmonary vascular resistance. The remodelling process entails increased migration and proliferation of smooth muscle cells (SMC) and deposition of the extracellular matrix (ECM). Focal adhesion complexes, which consist of transmembrane integrin receptors and cytoskeletal signalling proteins, link the ECM to the actin cytoskeleton. Alterations in activity or composition of focal adhesion complexes arising from changes in the ECM could potentiate PAH development. Paxillin is one of the most important focal adhesion proteins. It belongs to the family of LIM proteins, which mediate protein-protein interactions of signalling and cytoskeletal proteins as well as transcription factors.
Here, we examined the expression and activity of paxillin in iPAH using quantitative (q)RT-PCR, Western blotting, immunohistochemistry, and adhesion studies. We detected an increased expression of paxillin in lungs of iPAH patients (n=5) compared with controls (n=6, transplant donors) on both mRNA and protein levels. Immunohistochemical analysis demonstrated selective localisation of paxillin in pulmonary arterial SMC (PASMC). Immunofluorescence of human primary PASMC revealed that paxillin knock-down led to alterations in the cytoskeleton and consequently to a reduced adhesion of these cells as showed by adhesion assays. To explore the molecular mechanisms of the transcriptional regulation of human paxillin, we subjected PASMC to hypoxia (1% O2). In comparison to normoxic conditions, paxillin was higher expressed following 24 hours of hypoxic exposure. Knockdown of HIF-1a significantly reduced expression of paxillin under hypoxia demonstrating HIF-dependent regulation of paxillin.
Paxillin has previously been documented to be involved in cell spreading and migration, a feature characteristic for vascular remodelling. This is however the first report that indicates the involvement of paxillin in vascular remodelling in the lung, and its association with human iPAH disease.
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Acta Physiologica 2009; Volume 195, Supplement 669 :P394