RhoA and Rho Kinase Activation in Human Pulmonary Hypertension

• DOI: 10.1164/rccm.200805-691oc
• Publication Date: 2009-03-19T20:52:56Z
• Authors: Christophe Guilluy; Saadia Eddahibi; Christian Agard; Christophe Guigna...; Mohamed Izikki; Ly Tu; Laurent Savale; Marc Humbert; Elie Fadel; Serge Adnot; Gervaise Loirand; Pierre Pacaud
• Keywords: Fasudil; Rho kinase inhibitor

Rationale: The complex and multifactorial pathogenesis of pulmonary hypertension (PH) involves constriction, remodeling, in situ thrombosis vessels. Both serotonin (5-HT) Rho kinase signaling may contribute to these alterations.Objectives: To investigate possible links between the 5-HT transporter (5-HTT) RhoA/Rho pathways, as well their involvement progression human experimental PH.Methods: Biochemical functional analyses lungs, platelets, artery smooth muscle cells (PA-SMCs) from patients with idiopathic PH (iPH) 5-HTT overexpressing mice.Measurements Main Results: Lungs, PA-SMCs iPH were characterized by marked elevation RhoA activities a strong increase binding indicating serotonylation. inhibitor fluoxetine type 2 transglutaminase monodansylcadaverin prevented 5-HT–induced serotonylation activation, proliferation that was also inhibited fasudil. Increased activity, observed lungs SM22–5-HTT+mice, which overexpress spontaneously develop PH. Treatment SM22–5-HTT+ mice either fasudil or limited activation.Conclusions: are increased iPH, association enhanced Direct 5-HTT/RhoA/Rho pathway 5-HT–mediated PA-SMC platelet activation during identify promising target for new treatments against