title: Fluoxetine inhibits monocrotaline-induced pulmonary arterial remodeling involved in inhibition of RhoA-Rho kinase and Akt signalling pathways in rats.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, China Medical University, No. 92, the 2nd North Road, Heping District, Shenyang, 110001, China.
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Bai
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Zhang
authors.forename: Ying-Xian
authors.initials: YX
authors.lastname: Sun
authors.forename: Huai-Liang
authors.initials: HL
authors.lastname: Wang
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D065627:Familial Primary Pulmonary Hypertension; D005473:Fluoxetine / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D016686:Monocrotaline; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D005473:Fluoxetine; D007527:Isoenzymes; D016686:Monocrotaline; D051057:Proto-Oncogene Proteins c-akt; D017367:Selective Serotonin Reuptake Inhibitors; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; C494920:Akt1 protein, rat; C580818:ROCK2 protein, rat