Arginase inhibition protects against hypoxia‑induced pulmonary arterial hypertension

Jiang,Wenjin; Sun,Bolin; Song,Xuepeng; Zheng,Yanbo; Wang,Ligang; Wang,Tao; Liu,Sheng

doi:10.3892/mmr.2015.3994

Arginase inhibition protects against hypoxia‑induced pulmonary arterial hypertension

Authors:
- Wenjin Jiang
- Bolin Sun
- Xuepeng Song
- Yanbo Zheng
- Ligang Wang
- Tao Wang
- Sheng Liu
View Affiliations

Affiliations: Department of Interventional Radiology, Yantai Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
Published online on: June 24, 2015 https://doi.org/10.3892/mmr.2015.3994
Pages: 4743-4749

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to determine the role of arginase (Arg) in pulmonary arterial hypertension (PAH). In vitro, human pulmonary artery smooth muscle cells (HPASMCs) were cultured under hypoxic conditions with, or without, the Arg inhibitor, S‑(2‑boronoethyl)‑l‑cysteine (BEC), for 48 h, following which the proliferation of the HPASMCs was determined using MTT and cell counting assays. For the in vivo investigation, 30 male rats were randomly divided into the following three groups (n=10 per group): i) control group, ii) PAH group and iii) BEC group, in which the right ventricle systolic pressure (RVSP) of the rats was assessed. The levels of cyclin D1, cyclin‑dependent kinase (CDK)4 and p27 were measured in vitro and in vivo. The phosphorylation levels of Akt and extracellular‑related kinase (ERK) were also measured in HPASMCs. In vitro, compared with the hypoxia group, Arg inhibition reduced HPASMC proliferation and reduced the expression levels of cyclin D1, CDK4, phosphorylated (p‑)Akt and p‑ERK. By contrast, Arg inhibition increased the expression of p27. In vivo, compared with the control group, the expression levels of cyclin D1 and CDK4 were reduced in the PAH group, however, the expression of p27 and the RVSP increased. In the BEC group, the opposite effects were observed. Therefore, it was suggested that Arg inhibition may reduce the RVSP of PAH rats and reduce HPASMC proliferation by decreasing the expression levels of cyclin D1 and CDK4, increasing the expression of p27, and partly reducing the phosphorylation of Akt and ERK.

View Figures

View References

1	Frumkin LR: The pharmacological treatment of pulmonary arterial hypertension. Pharmacol Rev. 64:583–620. 2012. View Article : Google Scholar : PubMed/NCBI
2	Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O and Voelkel NF: Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 43(Suppl 12): 13S–24S. 2004. View Article : Google Scholar : PubMed/NCBI
3	Orlandi A, Bochaton-Piallat ML, Gabbiani G and Spagnoli LG: Aging, smooth muscle cells and vascular pathobiology: Implications for atherosclerosis. Atherosclerosis. 188:221–230. 2006. View Article : Google Scholar : PubMed/NCBI
4	Luo Y, Xu DQ, Dong HY, Zhang B, Liu Y, Niu W, Dong MQ and Li ZC: Tanshinone iia inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation via Akt/Skp2/p27-associated pathway. PLoS One. 8:e567742013. View Article : Google Scholar : PubMed/NCBI
5	Stenmark KR, Fagan KA and Frid MG: Hypoxia-induced pulmonary vascular remodeling: Cellular and molecular mechanisms. Circ Res. 99:675–691. 2006. View Article : Google Scholar : PubMed/NCBI
6	Vasa M, Fichtlscherer S, Adler K, Aicher A, Martin H, Zeiher AM and Dimmeler S: Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation. 103:2885–2890. 2001. View Article : Google Scholar : PubMed/NCBI
7	Sudar E, Dobutovic B, Soskic S, Mandusic V, Zakula Z, Misirkic M, Vucicevic L, Janjetovic K, Trajkovic V, Mikhailidis DP, et al: Regulation of inducible nitric oxide synthase activity/expression in rat hearts from ghrelin-treated rats. J Physiol Biochem. 67:195–204. 2011. View Article : Google Scholar
8	Isenovic ER, Meng Y, Divald A, Milivojevic N and Sowers JR: Role of phosphatidylinositol 3-kinase/akt pathway in angiotensin ii and insulin-like growth factor-1 modulation of nitric oxide synthase in vascular smooth muscle cells. Endocrine. 19:287–292. 2002. View Article : Google Scholar
9	Kaneko FT, Arroliga AC, Dweik RA, Comhair SA, Laskowski D, Oppedisano R, Thomassen MJ and Erzurum SC: Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension. Am J Respir Crit Care Med. 158:917–923. 1998. View Article : Google Scholar : PubMed/NCBI
10	Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D and Wallwork J: Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet. 338:1173–1174. 1991. View Article : Google Scholar : PubMed/NCBI
11	Ribeiro MO, Antunes E, de Nucci G, Lovisolo SM and Zatz R: Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension. Hypertension. 20:298–303. 1992. View Article : Google Scholar : PubMed/NCBI
12	Nagaya N, Uematsu M, Oya H, Sato N, Sakamaki F, Kyotani S, Ueno K, Nakanishi N, Yamagishi M and Miyatake K: Short-term oral administration of l-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension. Am J Respir Crit Care Med. 163:887–891. 2001. View Article : Google Scholar : PubMed/NCBI
13	Mori M and Gotoh T: Regulation of nitric oxide production by arginine metabolic enzymes. Biochem Biophys Res Commun. 275:715–719. 2000. View Article : Google Scholar : PubMed/NCBI
14	Wei LH, Wu G, Morris SM Jr and Ignarro LJ: Elevated arginase I expression in rat aortic smooth muscle cells increases cell proliferation. Proc Natl Acad Sci USA. 98:9260–9264. 2001. View Article : Google Scholar : PubMed/NCBI
15	Ckless K, Lampert A, Reiss J, Kasahara D, Poynter ME, Irvin CG, Lundblad LK, Norton R, van der Vliet A and Janssen-Heininger YM: Inhibition of arginase activity enhances inflammation in mice with allergic airway disease, in association with increases in protein s-nitrosylation and tyrosine nitration. J Immunol. 181:4255–4264. 2008. View Article : Google Scholar : PubMed/NCBI
16	Lu X, Murphy TC, Nanes MS and Hart CM: Ppar{gamma} regulates hypoxia-induced nox4 expression in human pulmonary artery smooth muscle cells through nf-{kappa B. Am J Physiol Lung Cell Mol Physiol. 299:L559–L566. 2010. View Article : Google Scholar : PubMed/NCBI
17	Crossno JT Jr, Garat CV, Reusch JE, Morris KG, Dempsey EC, McMurtry IF, Stenmark KR and Klemm DJ: Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling. Am J Physiol Lung Cell Mol Physiol. 292:L885–L897. 2007. View Article : Google Scholar
18	Corraliza IM, Campo ML, Soler G and Modolell M: Determination of arginase activity in macrophages: A micromethod. J Immunol Methods. 174:231–235. 1994. View Article : Google Scholar : PubMed/NCBI
19	Wang XP, Chen YG, Qin WD, Zhang W, Wei SJ, Wang J, Liu FQ, Gong L, An FS and Zhang Y: Arginase i attenuates inflammatory cytokine secretion induced by lipopolysaccharide in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 31:1853–1860. 2011. View Article : Google Scholar : PubMed/NCBI
20	Kiss T and Kovacs K, Komocsi A, Tornyos A, Zalan P, Sumegi B, Gallyas F Jr and Kovacs K: Novel mechanisms of sildenafil in pulmonary hypertension involving cytokines/chemokines, MAP kinases and Akt. PLoS One. 9:e1048902014. View Article : Google Scholar : PubMed/NCBI
21	Xu W, Kaneko FT, Zheng S, Comhair SA, Janocha AJ, Goggans T, Thunnissen FB, Farver C, Hazen SL and Jennings C: Increased arginase ii and decreased no synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J. 18:1746–1748. 2004.PubMed/NCBI
22	Fagan KA, Morrissey B, Fouty BW, Sato K, Harral JW, Morris KG Jr, Hoedt-Miller M, Vidmar S, McMurtry IF and Rodman DM: Upregulation of nitric oxide synthase in mice with severe hypoxia-induced pulmonary hypertension. Respir Res. 2:306–313. 2001. View Article : Google Scholar : PubMed/NCBI
23	Champion HC, Bivalacqua TJ, Greenberg SS, Giles TD, Hyman AL and Kadowitz PJ: Adenoviral gene transfer of endothelial nitric-oxide synthase (enos) partially restores normal pulmonary arterial pressure in enos-deficient mice. Proc Natl Acad Sci USA. 99:13248–13253. 2002. View Article : Google Scholar : PubMed/NCBI
24	Owens GK: Regulation of differentiation of vascular smooth muscle cells. Physiol Rev. 75:487–517. 1995.PubMed/NCBI
25	Kadowaki M, Mizuno S, Demura Y, Ameshima S, Miyamori I and Ishizaki T: Effect of hypoxia and Beraprost sodium on human pulmonary arterial smooth muscle cell proliferation: the role of p27kip1. Respir Res. 8:772007. View Article : Google Scholar : PubMed/NCBI
26	Yu L, Quinn DA, Garg HG and Hales CA: Gene expression of cyclin-dependent kinase inhibitors and effect of heparin on their expression in mice with hypoxia-induced pulmonary hypertension. Biochem Biophys Res Commun. 345:1565–1572. 2006. View Article : Google Scholar : PubMed/NCBI
27	Dong Y, Sui L, Sugimoto K, Tai Y and Tokuda M: Cyclin D1-cdk4 complex, a possible critical factor for cell proliferation and prognosis in laryngeal squamous cell carcinomas. Int J Cancer. 95:209–215. 2001. View Article : Google Scholar : PubMed/NCBI
28	Sakamoto K, Ohki K, Saito M, Nakahara T and Ishii K: Small molecule cyclin-dependent kinase inhibitors protect against neuronal cell death in the ischemic-reperfused rat retina. J Ocul Pharmacol Ther. 27:419–425. 2011. View Article : Google Scholar : PubMed/NCBI
29	Toyoshima H and Hunter T: P27, a novel inhibitor of g1 cyclin-cdk protein kinase activity, is related to p21. Cell. 78:67–74. 1994. View Article : Google Scholar : PubMed/NCBI