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: Ya-Yun Wang, Yun Luan, Xue Zhang, Mei Lin, Zhao-Hua Zhang, Xiao-Bo Zhu, Yu Ma, Yi-Biao Wang
• Journal: Clinical and experimental medicine (Clin Exp Med) Vol. 14 Issue 3 Pg. 321-9 (Aug 2014) ISSN: 1591-9528 [Electronic] Italy
• PMID: 23771811 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Boronic Acids
• NF-kappa B
• Proliferating Cell Nuclear Antigen
• Proteasome Inhibitors
• Pyrazines
• Smad Proteins
• Transforming Growth Factor beta
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, rat
• Bortezomib

Topics

• Animals
• Blotting, Western
• Boronic Acids (administration & dosage)
• Bortezomib
• Disease Models, Animal
• Gene Expression Profiling
• Hypertension, Pulmonary (pathology)
• Immunohistochemistry
• Lung (pathology)
• Male
• NF-kappa B (analysis)
• Proliferating Cell Nuclear Antigen (analysis)
• Proteasome Inhibitors (administration & dosage)
• Pyrazines (administration & dosage)
• Rats, Wistar
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Smad Proteins (analysis)
• Transforming Growth Factor beta (analysis)
• Vascular Endothelial Growth Factor A (analysis)
• Vascular Remodeling (drug effects)