Background- 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. Here, we investigated 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 and Results- Lungs, platelets, and quiescent cultured pulmonary-artery smooth-muscle cells (PA-SMCs) from patients with idiopathic PH (iPH) were characterized by marked elevations in RhoA and Rho kinase activity and by a strong increase in serotonin binding to RhoA, compared to controls. 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 both PH progression and RhoA/Rho kinase activation.
Conclusions- RhoA and Rho kinase activities are increased in iPH, as a result of transglutaminase-mediated transamidation of RhoA by 5-HT internalized via 5-HTT. Direct involvement of this 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.
RhoA/Rho-kinase signaling: a therapeutic target in pulmonary hypertension