title: Proteasome inhibitor PS-341 attenuates flow-induced pulmonary arterial hypertension.
abstract: PS-341, a proteasome inhibitor, is suggested to prevent the vascular remodeling induced by high-flow pulmonary artery hypertension (PAH), but the mechanism remains unclear. The aim of the current study was to investigate the effects and possible mechanism of PS-341 on hypertension-induced vascular remodeling. Male Sprague-Dawley rats were subjected to surgical methods to produce a shunt model of PAH. Three days after the surgical procedure, the animals randomly assigned to four groups (n = 10 in each group): I: sham group; II: shunt group; III: vehicle; IV: treated group. Eight weeks postoperative, the hemodynamics data were measured through Swan-Ganz catheter; the protein expression level of proliferating cell nuclear antigen, nuclear factor-κB (NF-κB), inhibitor of nuclear factor-κB (I-κBα), transforming growth factor beta-β (TGF-β), drosophila mothers against decapentaplegic protein (Smad) and vascular endothelia growth factor (VEGF) were investigated by immunohistochemical and Western blotting; the mRNA expression level of Ubiquitin (Ub), Smad3, TGF-β1and Smad2 in lung were performed to detect by real-time reverse transcription-polymerase chain reaction analysis. The results showed that hemodynamic data and right ventricular hypertrophy were significantly improved (P < 0.05), the expression level of Ub, NF-κB, TGF-β1, Smad2 and VEGF were decreased (P < 0.05), but the level of I-κBα was increased in PS-341 treated group as compared with the shunt and vehicle groups (P < 0.05). In conclusion, the present study indicated that PS-341 could significantly improve the lung damage, attenuate pulmonary vascular remodeling induced by high blood PAH model. The mechanism may be mediated by inhibition of NF-κB and TGF-β/Smad signaling pathway and modulation the effect of VEGF.
authors.affiliation: Department of Pediatrics, The Second Hospital of Shandong University, 247#, Beiyuan Dajie, Jinan, 250033, China.
authors.forename: Ya-Yun
authors.initials: YY
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Luan
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.forename: Mei
authors.initials: M
authors.lastname: Lin
authors.forename: Zhao-Hua
authors.initials: ZH
authors.lastname: Zhang
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Zhu
authors.forename: Yu
authors.initials: Y
authors.lastname: Ma
authors.forename: Yi-Biao
authors.initials: YB
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006976:Hypertension, Pulmonary / Q000473:pathology*; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000032:analysis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D061988:Proteasome Inhibitors / Q000008:administration & dosage*; D011719:Pyrazines / Q000008:administration & dosage*; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051785:Smad Proteins / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D001897:Boronic Acids; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D061988:Proteasome Inhibitors; D011719:Pyrazines; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D000069286:Bortezomib