A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.: p130Cas Over-Expression in Pulmonary Hypertension
| Autor: | Tu, Ly, de Man, Frances, Girerd, Barbara, Huertas, Alice, Chaumais, Marie-Camille, Lecerf, Florence, François, Charlène, Perros, Frédéric, Dorfmüller, Peter, Fadel, Elie, Montani, David, Eddahibi, Saadia, Humbert, Marc, Guignabert, Christophe |
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| Přispěvatelé: | Guignabert, Christophe, Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
MESH: Signal Transduction
MESH: Epidermal Growth Factor MESH: Rats MESH: Pulmonary Artery MESH: Piperazines [SDV.BC]Life Sciences [q-bio]/Cellular Biology Signal transduction Pulmonary arterial hypertension MESH: Monocrotaline MESH: Protein Kinase Inhibitors MESH: Animals MESH: Endothelial Cells [SDV.BC] Life Sciences [q-bio]/Cellular Biology MESH: Mice Pulmonary vascular remodeling MESH: Quinolones MESH: Humans MESH: Fibroblast Growth Factor 2 MESH: Hypertension Pulmonary MESH: Platelet-Derived Growth Factor MESH: Myocytes Smooth Muscle MESH: Case-Control Studies MESH: Crk-Associated Substrate Protein MESH: Quinazolines MESH: Pyrimidines embryonic structures BCAR1 MESH: Disease Models Animal Growth factors MESH: Benzimidazoles |
| Zdroj: | American Journal of Respiratory and Critical Care Medicine American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, 2012, 186 (7), pp.666-76. ⟨10.1164/rccm.201202-0309OC⟩ |
| ISSN: | 1073-449X 1535-4970 |
| DOI: | 10.1164/rccm.201202-0309OC⟩ |
| Popis: | International audience; RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by pulmonary arterial muscularization due to excessive pulmonary vascular cell proliferation and migration, a phenotype dependent upon growth factors and activation of receptor tyrosine kinases (RTKs). p130(Cas) is an adaptor protein involved in several cellular signaling pathways that control cell migration, proliferation, and survival. OBJECTIVES: We hypothesized that in experimental and human PAH p130(Cas) signaling is overactivated, thereby facilitating the intracellular transmission of signal induced by fibroblast growth factor (FGF)2, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF). MEASUREMENTS AND MAIN RESULTS: In patients with PAH, levels of p130(Cas) protein and/or activity are higher in the serum, in the walls of distal pulmonary arteries, in cultured smooth muscle cells (PA-SMCs), and in pulmonary endothelial cells (P-ECs) than in control subjects. These abnormalities in the p130(Cas) signaling were also found in the chronically hypoxic mice and monocrotaline-injected rats as models of human PAH. We obtained evidence for the convergence and amplification of the growth-stimulating effect of the EGF-, FGF2-, and PDGF-signaling pathways via the p130(Cas) signaling pathway. We found that daily treatment with the EGF-R inhibitor gefitinib, the FGF-R inhibitor dovitinib, and the PDGF-R inhibitor imatinib started 2 weeks after a subcutaneous monocrotaline injection substantially attenuated the abnormal increase in p130(Cas) and ERK1/2 activation and regressed established pulmonary hypertension. CONCLUSIONS: Our findings demonstrate that p130(Cas) signaling plays a critical role in experimental and idiopathic PAH by modulating pulmonary vascular cell migration and proliferation and by acting as an amplifier of RTK downstream signals. |
| Databáze: | OpenAIRE |
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