Fluoxetine inhibits monocrotaline-induced pulmonary arterial remodeling involved in inhibition of RhoA--Rho kinase and Akt signalling pathways in rats

Introduction Pulmonary arterial hypertension (PAH) is characterized by a sustained and progressive increase in pulmonary arterial pressure with pathologic changes involving vasoconstriction, vascular remodeling, and inflammation, which may lead to [...]
Activation of the small GTPase Ras homolog gene family member A (RhoA) and Rho-associated kinase (ROCK) are important in the pathogenesis of pulmonary arterial hypertension (PAH). Selective serotonin reuptake inhibitors inhibit activation of RhoA and ROCK in vitro, and ameliorate PAH and pulmonary arterial remodeling in vivo. However, little is known about whether the RhoA-ROCK signalling pathway is involved in the treatment of PAH with fluoxetine in vivo. The aim of the present study was to investigate the involvement of the RhoA-ROCK signalling pathway in the protective effect of the selective serotonin reuptake inhibitor fluoxetine against monocrotaline (MCT)-induced pulmonary arterial remodeling. MCT was applied to establish PAH in male Wistar rats. Fluoxetine was administered by gastric gavage once a day for 21 d. The results showed that MCT induced pulmonary arterial remodeling, raised the serotonylation and membrane translocation of RhoA in the lungs, and increased serotonin transporter (5-HTT), RhoA, and ROCK2 expression, and extracellular signal-regulated kinase (ERK) and Akt phosphorylation in the pulmonary arteries and the lungs. Fluoxetine markedly inhibited these MCT-induced changes. The findings suggest that fluoxetine inhibits MCT-induced pulmonary arterial remodeling in rats by inhibition of the RhoA-ROCK and Akt signalling pathways. Key words: RhoA, Rho kinase, monocrotaline, serotonin transporter, fluoxetine, pulmonary arterial remodeling, Akt. L'activation de la proteine RhoA, une petite GTPase membre de la famille des homologues de Ras, et de ROCK, une kinase associee a ROCK, est importante a la pathogenese de l'hypertension arterielle pulmonaire (HAP). Les inhibiteurs selectifs de recapture de la serotonine peuvent inhiber l'activation de RhoA et ROCK in vitro et ameliorer l'HAP et le remodelage arteriel pulmonaire in vivo. Cependant, on ignore si la voie de signalisation RhoA-ROCK est impliquee dans le traitement de l'HAP in vivo par la fluoxetine. Le but de cette etude etait d'examiner l'implication de la voie de signalisation RhoA-ROCK dans l'effet protecteur exerce par la fluoxetine, un inhibiteur selectif de recapture de la serotonine, sur le remodelage arteriel pulmonaire induit par la monocrotaline (MCT). La MCT a ete donnee a des rats males Wistar afin d' etablir un etat d' HAP. La fluoxetine a ete administree par gavage gastrique une fois par jour pendant 21 jours. Les resultats ont revele que la MCT induisait un remodelage arteriel pulmonaire, accroissait la serotonylation et la translocation membranaire de RhoA dans les poumons et augmentait l' expression du 5-HTT, de RhoA et de ROCK ainsi que la phosphorylation de ERK et Akt dans les arteres pulmonaires et les poumons. La fluoxetine inhibait fortement ces changements induits par la MCT. Ces resultats suggerent que la fluoxetine a inhibe le remodelage arteriel pulmonaire induit par la MCT chez les rats et que ce phenomene impliquait l'inhibition des voies de signalisation RhoA-ROCK et Akt. Mots-cles : RhoA, Rho kinase, monocrotaline, transporteur de serotonine, fluoxetine, remodelage pulmonaire arteriel, Akt. [Traduit par la Redaction]