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RhoA and Rho Kinase Activation in Human Pulmonary Hypertension

Role of 5-HT Signaling

¹ Inserm, U915, Nantes, France; ² Université de Nantes, Faculté des Sciences, and ⁴ CHU Nantes, l'Institut du Thorax, Nantes, France; ³ Inserm, U651, Créteil, France; ⁵ Université Paris-Sud 11, Inserm, U764, Hôpital Antoine Béclère, AP-HP, Clamart, France; ⁶ Université Paris-Sud 11, UPRES EA 2705, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France; and ⁷ Hôpital Henri Mondor, AP-HP, Créteil, France

Correspondence and requests for reprints should be addressed to Pr. Pierre Pacaud, Ph.D., Inserm U915, Faculté de médecine, 4 rue Gaston Veil, 44035 Nantes cedex 1, France. E-mail: pierre.pacaud{at}univ-nantes.fr

Rationale: 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.

Objectives: 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.

Methods: 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.

Measurements and Main Results: 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.

Conclusions: 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.

Key Words: hypertension, pulmonary • muscle, smooth • Rho proteins • signal transduction • serotonin

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Animal studies suggest that activation of the RhoA pathway is a common and critical mechanism for the pathogenesis of pulmonary hypertension in diverse models, but data supporting this mechanism in human pulmonary hypertension are lacking. What This Study Adds to the Field We demonstrate that RhoA and Rho kinase activities are increased in human pulmonary artery smooth muscle cells from patients with pulmonary hypertension. This activation is due to transglutaminase-mediated transamidation of RhoA by intracellular 5-HT, which contributes to pulmonary artery smooth muscle cell proliferation.

 

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