RhoA and Rho Kinase Activation in Human Pulmonary Hypertension
| Autor: | Christophe Guilluy, Saadia Eddahibi, Marc Humbert, Elie Fadel, Gervaise Loirand, Mohamed Izikki, Pierre Pacaud, Laurent Savale, Christophe Guignabert, Ly Tu, Serge Adnot, Christian Agard |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Blood Platelets Male Pulmonary and Respiratory Medicine Serotonin medicine.medical_specialty RHOA Adolescent Hypertension Pulmonary Blotting Western Serotonylation Mice Transgenic Pulmonary Artery Critical Care and Intensive Care Medicine Muscle Smooth Vascular Pathogenesis Mice Young Adult Intensive care Internal medicine Animals Humans Medicine Rho-associated protein kinase Cells Cultured Cell Proliferation rho-Associated Kinases biology business.industry Cell growth Middle Aged medicine.disease Pulmonary hypertension Enzyme Activation Disease Models Animal Endocrinology Vasoconstriction Cancer research biology.protein Female Signal transduction rhoA GTP-Binding Protein business Signal Transduction |
| Zdroj: | American Journal of Respiratory and Critical Care Medicine. 179:1151-1158 |
| ISSN: | 1535-4970 1073-449X |
| Popis: | The complex and multifactorial pathogenesis of pulmonary hypertension (PH) involves constriction, remodeling, and in situ thrombosis of pulmonary vessels. Both serotonin (5-HT) and Rho kinase signaling may contribute to these alterations.To investigate possible links between the 5-HT transporter (5-HTT) and RhoA/Rho kinase pathways, as well as their involvement in the progression of human and experimental PH.Biochemical and functional analyses of lungs, platelets, and pulmonary artery smooth muscle cells (PA-SMCs) from patients with idiopathic PH (iPH) and 5-HTT overexpressing mice.Lungs, platelets, and PA-SMCs from patients with iPH were characterized by marked elevation in RhoA and Rho kinase activities and a strong increase in 5-HT binding to RhoA indicating RhoA serotonylation. The 5-HTT inhibitor fluoxetine and the type 2 transglutaminase inhibitor monodansylcadaverin prevented 5-HT-induced RhoA serotonylation and RhoA/Rho kinase activation, as well as 5-HT-induced proliferation of PA-SMCs from iPH patients that was also inhibited by the Rho kinase inhibitor fasudil. Increased Rho kinase activity, RhoA activation, and RhoA serotonylation were also observed in lungs from SM22-5-HTT(+)mice, which overexpress 5-HTT in smooth muscle and spontaneously develop PH. Treatment of SM22-5-HTT(+) mice with either fasudil or fluoxetine limited PH progression and RhoA/Rho kinase activation.RhoA and Rho kinase activities are increased in iPH, in association with enhanced RhoA serotonylation. Direct involvement of the 5-HTT/RhoA/Rho kinase signaling pathway in 5-HT-mediated PA-SMC proliferation and platelet activation during PH progression identify RhoA/Rho kinase signaling as a promising target for new treatments against PH. |
| Databáze: | OpenAIRE |
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