The effect of PS-341 on pulmonary vascular remodeling in high blood flow-induced pulmonary hypertension

Zhang,Xue; Wang,Zong-Shuai; Luan,Yun; Lin,Mei; Zhu,Xiao-Bo; Ma,Yu; Zhang,Zhao-Hua; Wang,Yi-Biao

doi:10.3892/ijmm.2013.1562

The effect of PS-341 on pulmonary vascular remodeling in high blood flow-induced pulmonary hypertension

Authors:
- Xue Zhang
- Zong-Shuai Wang
- Yun Luan
- Mei Lin
- Xiao-Bo Zhu
- Yu Ma
- Zhao-Hua Zhang
- Yi-Biao Wang
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Affiliations: Department of Pediatrics, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China, Central Research Laboratory, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
Published online on: November 21, 2013 https://doi.org/10.3892/ijmm.2013.1562
Pages: 105-110

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Abstract

The aim of the present study was to investigate the effects of PS-341 on vascular remodeling in an experimental rat model of high blood flow-induced pulmonary arterial hypertension (PAH), as well as to elucidate its mechanisms of action. We established the PAH model by a surgical method that implanted a left-to-right shunt. Three days post-surgery, the animals were randomly assigned to 3 groups (n=15 in each group): sham-operated (control), shunt (model) and PS-341 (treated) groups. Eight weeks post-surgery, hemodynamic parameters were significantly improved in the PS-341 group compared with the shunt group (P<0.05). Immunohistochemical analysis indicated that the expression levels of ubiquitin and nuclear factor-κB (NF-κB) p65 were significantly higher in the shunt group compared with the sham-operated group (P<0.05). Semi-quantitative western blot analysis further confirmed that the levels of ubiquitin and NF-κB p65 were decreased, while those of IκB-α (an inhibitor of NF-κB) were significantly increased in the PS-341 group compared with the shunt group (P<0.05). In conclusion, PS-341 attenuates high blood flow-induced pulmonary artery remodeling in rats via inhibition of the NF-κB pathway.

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1	Li B, Yang L, Shen J, Wang C and Jiang Z: The antiproliferative effect of sildenafil on pulmonary artery smooth muscle cells is mediated via upregulation of mitogen-activated protein kinase phosphatase-1 and degradation of extracellular signal-regulated kinase 1/2 phosphorylation. Anesth Analg. 105:1034–1041. 2007. View Article : Google Scholar
2	Ohata Y, Ogata S, Nakanishi K, et al: Expression of P2X4R mRNA and protein in rats with hypobaric hypoxia-induced pulmonary hypertension. Circ J. 75:945–954. 2011. View Article : Google Scholar : PubMed/NCBI
3	Yildiz P: Molecular mechanisms of pulmonary hypertension. Clin Chim Acta. 403:9–16. 2009. View Article : Google Scholar
4	Can MM, Tanboğa IH, Demircan HC, et al: Enhanced hemostatic indices in patients with pulmonary arterial hypertension: an observational study. Thromb Res. 126:280–282. 2010. View Article : Google Scholar : PubMed/NCBI
5	Junbao D, Hui Y, Bing W, Jian L, Jianguang Q and Chaoshu T: Effect of L-arginine on collagen of high flow-induced pulmonary arterial remodeling. Circ J. 69:603–608. 2005. View Article : Google Scholar : PubMed/NCBI
6	Baber SR, Deng W, Master RG, et al: Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction. Am J Physiol Heart Circ Physiol. 292:H1120–H1128. 2007. View Article : Google Scholar
7	Zhao YD, Courtman DW, Ng DS, et al: Microvascular regeneration in established pulmonary hypertension by angiogenic gene transfer. Am J Respir Cell Mol Biol. 35:182–189. 2006. View Article : Google Scholar : PubMed/NCBI
8	Sun Y, Tian Y, Prabha M, et al: Effects of sulfur dioxide on hypoxic pulmonary vascular structural remodeling. Lab Invest. 90:68–82. 2010. View Article : Google Scholar : PubMed/NCBI
9	Cuifen Z, Lijuan W, Li G, Wei X, Zhiyu W and Fuhai L: Changes and distributions of peptides derived from proadrenomedullin in left-to-right shunt pulmonary hypertension of rats. Circ J. 72:476–481. 2008. View Article : Google Scholar : PubMed/NCBI
10	McMurtry MS, Bonnet S, Wu X, et al: Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res. 95:830–840. 2004. View Article : Google Scholar : PubMed/NCBI
11	Li M, Dong X, Liu Y, Sun X, Li Z and He J: Inhibition of ubiquitin proteasome function suppresses proliferation of pulmonary artery smooth muscle cells. Naunyn Schmiedebergs Arch Pharmacol. 384:517–523. 2011. View Article : Google Scholar : PubMed/NCBI
12	Takami Y, Nakagami H, Morishita R, et al: Ubiquitin carboxyl-terminal hydrolase L1, a novel deubiquitinating enzyme in the vasculature, attenuates NF-kappaB activation. Arterioscler Thromb Vasc Biol. 27:2184–2190. 2007. View Article : Google Scholar : PubMed/NCBI
13	Ma Y, Chen B, Liu D, et al: MG132 treatment attenuates cardiac remodeling and dysfunction following aortic banding in rats via the NF-κB/TGFβ1 pathway. Biochem Pharmacol. 81:1228–1236. 2011.PubMed/NCBI
14	Jin UH, Suh SJ, Chang HW, et al: Tanshinone IIA from Salvia miltiorrhiza BUNGE inhibits human aortic smooth muscle cell migration and MMP-9 activity through AKT signaling pathway. J Cell Biochem. 104:15–26. 2008.
15	Djordjevic T, Hess J, Herkert O, Görlach A and BelAiba RS: Rac regulates thrombin-induced tissue factor expression in pulmonary artery smooth muscle cells involving the nuclear factor-kappaB pathway. Antioxid Redox Signal. 6:713–720. 2004. View Article : Google Scholar
16	Meiners S, Dreger H, Fechner M, et al: Suppression of cardiomyocyte hypertrophy by inhibition of the ubiquitin-proteasome system. Hypertension. 51:302–308. 2008. View Article : Google Scholar : PubMed/NCBI
17	Wrana JL, Attisano L, Wieser R, Ventura F and Massagué J: Mechanism of activation of the TGF-beta receptor. Nature. 370:341–347. 1994. View Article : Google Scholar : PubMed/NCBI
18	Li W, Jin HF, Liu D, et al: Hydrogen sulfide induces apoptosis of pulmonary artery smooth muscle cell in rats with pulmonary hypertension induced by high pulmonary blood flow. Chin Med J (Engl). 122:3032–3038. 2009.PubMed/NCBI
19	Luan Y, Zhang ZH, Wei DE, et al: Implantation of mesenchymal stem cells improves right ventricular impairments caused by experimental pulmonary hypertension. Am J Med Sci. 343:402–406. 2012. View Article : Google Scholar : PubMed/NCBI
20	Wang YY, Luan Y, Zhang X, et al: Proteasome inhibitor PS-341 attenuates flow-induced pulmonary arterial hypertension. Clin Exp Med. June.16–2013.(Epub ahead of print).
21	Depre C, Wang Q, Yan L, et al: Activation of the cardiac proteasome during pressure overload promotes ventricular hypertrophy. Circulation. 114:1821–1818. 2006. View Article : Google Scholar : PubMed/NCBI
22	Naujokat C and Hoffmann S: Role and function of the 26S proteasome in proliferation and apoptosis. Lab Invest. 82:965–980. 2002. View Article : Google Scholar : PubMed/NCBI
23	Doll D, Sarikas A, Krajcik R and Zolk O: Proteomic expression analysis of cardiomyocytes subjected to proteasome inhibition. Biochem Biophys Res Commun. 353:436–442. 2007. View Article : Google Scholar : PubMed/NCBI
24	Voutsadakis IA: Ubiquitination and the Ubiquitin-Proteasome System as regulators of transcription and transcription factorsin epithelial mesenchymal transition of cancer. Tumour Biol. 33:897–910. 2012. View Article : Google Scholar
25	Moore BS, Eustáquio AS and McGlinchey RP: Advances in and applications of proteasome inhibitors. Curr Opin Chem Biol. 12:434–440. 2008. View Article : Google Scholar : PubMed/NCBI
26	Razeghi P, Baskin KK, Sharma S, et al: Atrophy, hypertrophy, and hypoxemia induce transcriptional regulators of the ubiquitin proteasome system in the rat heart. Biochem Biophys Res Commun. 342:361–364. 2006. View Article : Google Scholar : PubMed/NCBI
27	Meiners S, Laule M, Rother W, et al: Ubiquitin-proteasome pathway as a new target for the prevention of restenosis. Circulation. 105:483–489. 2002. View Article : Google Scholar : PubMed/NCBI
28	Barringhaus KG and Matsumura ME: The proteasome inhibitor lactacystin attenuates growth and migration of vascular smooth muscle cells and limits the response to arterial injury. Exp Clin Cardiol. 12:119–124. 2007.PubMed/NCBI
29	Sanchez-Ponce D, Tapia M, Muñoz A and Garrido JJ: New role of IKK alpha/beta phosphorylated I kappa B alpha in axon outgrowth and axon initial segment development. Mol Cell Neurosci. 37:832–844. 2008. View Article : Google Scholar : PubMed/NCBI
30	Farber HW and Loscalzo J: Pulmonary arterial hypertension. N Engl J Med. 351:1655–1665. 2004. View Article : Google Scholar : PubMed/NCBI
31	Kee K and Naughton MT: Heart failure and the lung. Circ J. 74:2507–2516. 2010. View Article : Google Scholar : PubMed/NCBI
32	Iyer SS, Co C and Rojas M: Mesenchymal stem cells and inflammatory lung diseases. Panminerva Med. 51:5–16. 2009.PubMed/NCBI
33	Baber SR, Deng W, Master RG, et al: Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction. Am J Physiol Heart Circ Physiol. 292:H1120–H1128. 2007. View Article : Google Scholar
34	Patel KM, Crisostomo P, Lahm T, et al: Mesenchymal stem cells attenuate hypoxic pulmonary vasoconstriction by a paracrine mechanism. J Surg Res. 143:281–285. 2007. View Article : Google Scholar : PubMed/NCBI
35	Diller GP, van Eijl S, Okonko DO, et al: Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation. 117:3020–3030. 2008. View Article : Google Scholar : PubMed/NCBI
36	Daroczi B, Kari G, Ren Q, Dicker AP and Rodeck U: Nuclear factor kappa B inhibitors alleviate and the proteasome inhibitor PS-341 exacerbates radiation toxicity in zebrafish embryos. Mol Cancer Ther. 8:2625–2634. 2009. View Article : Google Scholar
37	Zavrski I, Kleeberg L, Kaiser M, et al: Proteasome as an emerging therapeutic target in cancer. Curr Pharm Des. 13:471–485. 2007. View Article : Google Scholar : PubMed/NCBI
38	Erl W, Hansson GK, de Martin R, Draude G, Weber KS and Weber C: Nuclear factor-kappa B regulates induction of apoptosis and inhibitor of apoptosis protein-1 expression in vascular smooth muscle cells. Circ Res. 84:668–677. 1999. View Article : Google Scholar : PubMed/NCBI
39	Grassia G, Maddaluno M, Musilli C, et al: The I{kappa}B kinase inhibitor nuclear factor-{kappa}B essential modulator-binding domain peptide for inhibition of injury-induced neointimal formation. Arterioscler Thromb Vasc Biol. 30:2458–2466. 2010.