Skip to main content
SpringerLink
Log in

RETRACTED ARTICLE: Arginase inhibitor attenuates pulmonary artery hypertension induced by hypoxia

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

This article was retracted on 02 September 2023

This article has been updated

Abstract

Hypoxia-induced pulmonary arterial hypertension (HPAH) is a refractory disease characterized by increased proliferation of pulmonary vascular smooth cells and progressive pulmonary vascular remodeling. The level of nitric oxide (NO), a potential therapeutic vasodilator, is low in PAH patients. l-arginine can be converted to either beneficial NO by nitric oxide synthases or to harmful urea by arginase. In the present study, we aimed to investigate whether an arginase inhibitor, S-(2-boronoethyl)-l-cysteine ameliorates HPAH in vivo and vitro. In a HPAH mouse model, we assessed right ventricle systolic pressure (RVSP) by an invasive method, and found that RSVP was elevated under hypoxia, but was attenuated upon arginase inhibition. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured under hypoxic conditions, and their proliferative capacity was determined by cell counting and flow cytometry. The levels of cyclin D1, p27, p-Akt, and p-ERK were detected by RT-PCR or Western blot analysis. Compared to hypoxia group, arginase inhibitor inhibited HPASMCs proliferation and reduced the levels of cyclin D1, p-Akt, p-ERK, while increasing p27 level. Moreover, in mouse models, compared to control group, hypoxia increased cyclin D1 expression but reduced p27 expression, while arginase inhibitor reversed the effects of hypoxia. Taken together, these results suggest that arginase plays an important role in increased proliferation of HPASMCs induced by hypoxia and it is a potential therapeutic target for the treatment of pulmonary hypertensive disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Change history

Abbreviations

HPAH:

Hypoxia-induced pulmonary arterial hypertension

NO:

Nitric oxide

NOS:

Nitric oxide synthases

RVSP:

Right ventricle systolic pressure

HPASMCs:

Human pulmonary artery smooth muscle cells

PAH:

Pulmonary arterial hypertension

VSMCs:

Vascular smooth muscle cells

BEC:

S-(2-boronoethyl)-l-cysteine

References

  1. Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M (2004) Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43:13S–24S

    Article  CAS  PubMed  Google Scholar 

  2. Orlandi A, Bochaton-Piallat ML, Gabbiani G, Spagnoli LG (2006) Aging, smooth muscle cells and vascular pathobiology: implications for atherosclerosis. Atherosclerosis 188:221–230

    Article  CAS  PubMed  Google Scholar 

  3. Stenmark KR, Fagan KA, Frid MG (2006) Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res 99:675–691

    Article  CAS  PubMed  Google Scholar 

  4. Luo Y, Xu DQ, Dong HY, Zhang B, Liu Y, Niu W, Dong MQ, Li ZC (2013) Tanshinone iia inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation via akt/skp2/p27-associated pathway. PLoS One 8:e56774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Vasa M, Fichtlscherer S, Adler K, Aicher A, Martin H, Zeiher AM, Dimmeler S (2001) Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 103:2885–2890

    Article  CAS  PubMed  Google Scholar 

  6. Sudar E, Dobutovic B, Soskic S, Mandusic V, Zakula Z, Misirkic M, Vucicevic L, Janjetovic K, Trajkovic V, Mikhailidis DP, Isenovic ER (2011) Regulation of inducible nitric oxide synthase activity/expression in rat hearts from ghrelin-treated rats. J Physiol Biochem 67:195–204

    Article  CAS  PubMed  Google Scholar 

  7. Isenovic ER, Meng Y, Divald A, Milivojevic N, Sowers JR (2002) 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

    Article  CAS  PubMed  Google Scholar 

  8. Kaneko FT, Arroliga AC, Dweik RA, Comhair SA, Laskowski D, Oppedisano R, Thomassen MJ, Erzurum SC (1998) Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension. Am J Respir Crit Care Med 158:917–923

    Article  CAS  PubMed  Google Scholar 

  9. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J (1991) Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 338:1173–1174

    Article  CAS  PubMed  Google Scholar 

  10. Ribeiro MO, Antunes E, de Nucci G, Lovisolo SM, Zatz R (1992) Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension. Hypertension 20:298–303

    Article  CAS  PubMed  Google Scholar 

  11. Nagaya N, Uematsu M, Oya H, Sato N, Sakamaki F, Kyotani S, Ueno K, Nakanishi N, Yamagishi M, Miyatake K (2001) 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

    Article  CAS  PubMed  Google Scholar 

  12. Mori M, Gotoh T (2000) Regulation of nitric oxide production by arginine metabolic enzymes. Biochem Biophys Res Commun 275:715–719

    Article  CAS  PubMed  Google Scholar 

  13. Ckless K, Lampert A, Reiss J, Kasahara D, Poynter ME, Irvin CG, Lundblad LK, Norton R, van der Vliet A, Janssen-Heininger YM (2008) 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

    Article  CAS  PubMed  Google Scholar 

  14. Nelin LD, Chicoine LG, Reber KM, English BK, Young TL, Liu Y (2005) Cytokine-induced endothelial arginase expression is dependent on epidermal growth factor receptor. Am J Respir Cell Mol Biol 33(4):394–401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chen B, Calvert AE, Cui H, Nelin LD (2009) Hypoxia promotes human pulmonary artery smooth muscle cell proliferation through induction of arginase. Am J Physiol Lung Cell Mol Physiol 297:1151–1159

    Article  Google Scholar 

  16. Lu X, Murphy TC, Nanes MS, Hart CM (2010) PPARγ regulates hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells through nf-κB. Am J Physiol Lung Cell Mol Physiol 299:L559–L566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Corraliza IM, Campo ML, Soler G, Modolell M (1994) Determination of arginase activity in macrophages: a micromethod. J Immunol Methods 174:231–235

    Article  CAS  PubMed  Google Scholar 

  18. Chen H, Strappe P, Chen S, Wang LX (2014) Endothelial progenitor cells and pulmonary arterial hypertension. Heart Lung Circ 6:S1443–S9506

    Google Scholar 

  19. Pugliese SC, Poth JM, Fini MA, Olschewski A, El Kasmi KC (2015) Stenmark KR. The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes. Am J Physiol Lung Cell Mol Physiol 308(3):L229–L252

    Article  CAS  PubMed  Google Scholar 

  20. Xu W, Kaneko FT, Zheng S, Comhair SA, Janocha AJ, Goggans T, Thunnissen FB, Farver C, Hazen SL, Jennings C, Dweik RA, Arroliga AC, Erzurum SC (2004) Increased arginase ii and decreased no synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J 18:1746–1748

    Article  CAS  PubMed  Google Scholar 

  21. Fagan KA, Morrissey B, Fouty BW, Sato K, Harral JW, Morris KG Jr, Hoedt-Miller M, Vidmar S, McMurtry IF, Rodman DM (2001) Upregulation of nitric oxide synthase in mice with severe hypoxia-induced pulmonary hypertension. Respir Res 2:306–313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Champion HC, Bivalacqua TJ, Greenberg SS, Giles TD, Hyman AL, Kadowitz PJ (2002) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang XP, Chen YG, Qin WD, Zhang W, Wei SJ, Wang J, Liu FQ, Gong L, An FS, Zhang Y, Chen ZY, Zhang MX (2011) Arginase i attenuates inflammatory cytokine secretion induced by lipopolysaccharide in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 31:1853–1860

    Article  CAS  PubMed  Google Scholar 

  24. Colleluori DM, Ash DE (2001) Classical and slow-binding inhibitors of human type II arginase. Biochemistry 40(31):9356–9362

    Article  CAS  PubMed  Google Scholar 

  25. Owens GK (1995) Regulation of differentiation of vascular smooth muscle cells. Physiol Rev 75:487–517

    Article  CAS  PubMed  Google Scholar 

  26. Yu L, Quinn DA, Garg HG, Hales CA (2006) 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

    Article  CAS  PubMed  Google Scholar 

  27. Dong Y, Sui L, Sugimoto K, Tai Y, Tokuda M (2001) Cyclin D1-CDK4 complex, a possible critical factor for cell proliferation and prognosis in laryngeal squamous cell carcinomas. Int J Cancer 95:209–215

    Article  CAS  PubMed  Google Scholar 

  28. Zhao Y, Lv M, Lin H, Cui Y, Wei X, Qin Y, Kohama K, Gao Y (2013) Rho-associated protein kinase isoforms stimulate proliferation of vascular smooth muscle cells through ERK and induction of cyclin D1 and PCNA. Biochem Biophys Res Commun 432(3):488–493

    Article  CAS  PubMed  Google Scholar 

  29. Toyoshima H, Hunter T (1994) P27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78:67–74

    Article  CAS  PubMed  Google Scholar 

  30. Vascul Pharmacol (2007) Antiproliferative activity of NQ304, a synthetic 1,4-naphthoquinone, is mediated via the suppressions of the PI3 K/Akt and ERK1/2 signaling pathways in PDGF-BB-stimulated vascular smooth muscle cells. Vascul Pharmacol 46(1):43–51

    Article  Google Scholar 

  31. Kövamees O, Shemyakin A, Pernow J (2014) Effect of arginase inhibition on ischemia-reperfusion injury in patients with coronary artery disease with and without diabetes mellitus. PLoS One 9(7):e103260

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported by the fund from Projects of technology development program in Shandong Province, P R China (No. 2014GSF121015) and Projects of medical and health technology development program in Shandong Province (No. 2014WS0343).

Author information

Authors and Affiliations

  1. Department of Respiration, Jinan Central Hospital Affiliated to Shandong University, 105 JieFang Rd, Ji’nan, 250013, Shandong, China

    YanBiao Chu, HongChao Wang, PingDong Jia, WenBin Gong & ChunYan Xing

  2. Department of Surgery, Qilu Hospital, Shandong University, Ji’nan, 250012, Shandong, China

    XiaoYing XiangLi

  3. Department of General Surgery, The Fourth People’s Hospital of Ji’nan, The Second Affiliated Hospital of Tai Shan Medical College, Ji’nan, 250031, China

    Hu Niu

  4. Department of Critical Care Medicine, Qilu Hospital, Shandong University, Ji’nan, 250012, Shandong, China

    DaWei Wu & WeiDong Qin

Authors
  1. YanBiao Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. XiaoYing XiangLi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hu Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. HongChao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. PingDong Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. WenBin Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. DaWei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. WeiDong Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. ChunYan Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to ChunYan Xing.

Ethics declarations

Conflict of interest

None.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chu, Y., XiangLi, X., Niu, H. et al. RETRACTED ARTICLE: Arginase inhibitor attenuates pulmonary artery hypertension induced by hypoxia. Mol Cell Biochem 412, 91–99 (2016). https://doi.org/10.1007/s11010-015-2611-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-015-2611-z

Keywords

Search

Navigation