A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.: p130Cas Over-Expression in Pulmonary Hypertension

Abstract : 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.
Type de document :
Article dans une revue
American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, 2012, 186 (7), pp.666-76. 〈10.1164/rccm.201202-0309OC〉
Liste complète des métadonnées

Littérature citée [6 références]  Voir  Masquer  Télécharger

http://www.hal.inserm.fr/inserm-00905191
Contributeur : Christophe Guignabert <>
Soumis le : dimanche 17 novembre 2013 - 14:46:21
Dernière modification le : mercredi 29 novembre 2017 - 10:29:54
Document(s) archivé(s) le : vendredi 7 avril 2017 - 23:54:20

Fichier

p130cas_court.pdf
Fichiers produits par l'(les) auteur(s)

Identifiants

Collections

Citation

Ly Tu, Frances De Man, Barbara Girerd, Alice Huertas, Marie-Camille Chaumais, et al.. A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.: p130Cas Over-Expression in Pulmonary Hypertension. American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, 2012, 186 (7), pp.666-76. 〈10.1164/rccm.201202-0309OC〉. 〈inserm-00905191〉

Partager

Métriques

Consultations de la notice

158

Téléchargements de fichiers

27