Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Veith, C; Marsh, LM; Wygrecka, M; Rutschmann, K; Seeger, W; Weissmann, N; Kwapiszewska, G.
Paxillin regulates pulmonary arterial smooth muscle cell function in pulmonary hypertension.
Am J Pathol. 2012; 181(5):1621-1633
Doi: 10.1016/j.ajpath.2012.07.026
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- Co-Autor*innen der Med Uni Graz
- Kwapiszewska-Marsh Grazyna
- Marsh Leigh
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- Abstract:
- Pulmonary hypertension (PH) is a fatal disease characterized by remodeling processes such as increased migration and proliferation of pulmonary arterial smooth muscle cells (PASMC), enhanced matrix deposition, and dysregulation of cytoskeletal proteins. However, the contribution of cytoskeletal proteins in PH is still not fully understood. In this study, we have used a yeast two-hybrid screen to identify novel binding partners of the cytoskeletal adaptor protein four-and-a-half LIM domains 1 (Fhl-1). This identified paxillin as a new Fhl-1 interacting partner, and consequently we assessed its contribution to vascular remodeling processes. Native protein-protein binding was confirmed by co-immunoprecipitation studies in murine and human PASMC. Both proteins co-localized in PASMC in vitro and in vivo. In lung samples from idiopathic pulmonary arterial hypertension patients, paxillin expression was increased on mRNA and protein levels. Laser-microdissection of murine intrapulmonary arteries revealed elevated paxillin expression in hypoxia-induced PH. Furthermore, hypoxia-dependent upregulation of paxillin was HIF-1α dependent. Silencing of paxillin expression led to decreased PASMC adhesion, proliferation, and increased apoptosis. Regulation of these processes occurred via Akt and Erk1/2 kinases. In addition, adhesion of PASMC to the extracellular matrix protein fibronectin was critically dependent on paxillin expression. To summarize, we identified paxillin as a new regulator protein of PASMC growth.
- Find related publications in this database (using NLM MeSH Indexing)
- Adult -
- Animals -
- Anoxia - complications
- Apoptosis -
- Cell Adhesion -
- Cell Proliferation -
- Disease Models, Animal -
- Enzyme Activation -
- Extracellular Signal-Regulated MAP Kinases - metabolism
- Female -
- Fibronectins - metabolism
- Focal Adhesion Protein-Tyrosine Kinases - metabolism
- Humans -
- Hypertension, Pulmonary - complications
- Intracellular Signaling Peptides and Proteins - metabolism
- LIM Domain Proteins - metabolism
- Lung - metabolism
- Male -
- Mice -
- Middle Aged -
- Muscle Proteins - metabolism
- Myocytes, Smooth Muscle - enzymology
- Paxillin - metabolism
- Phosphorylation -
- Protein Binding -
- Proto-Oncogene Proteins c-akt - metabolism
- Pulmonary Artery - pathology
- Signal Transduction -