Effects of 17β-estradiol and 2-methoxyestradiol on the oxidative stress-hypoxia inducible factor-1 pathway in hypoxic pulmonary hypertensive rats

Wang,Li; Zheng,Quan; Yuan,Yadong; Li,Yanpeng; Gong,Xiaowei

doi:10.3892/etm.2017.4243

Effects of 17β-estradiol and 2-methoxyestradiol on the oxidative stress-hypoxia inducible factor-1 pathway in hypoxic pulmonary hypertensive rats

Authors:
- Li Wang
- Quan Zheng
- Yadong Yuan
- Yanpeng Li
- Xiaowei Gong
View Affiliations

Affiliations: Department of Respiratory Disease and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
Published online on: March 20, 2017 https://doi.org/10.3892/etm.2017.4243
Pages: 2537-2543

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 investigate the effects of 17β-estradiol (E2) and 2-methoxyestradiol (2ME) on the oxidative stress-hypoxia inducible factor-1 (OS-HIF-1) pathway in hypoxic pulmonary hypertensive rats. Female Sprague‑Dawley rats were divided randomly into 4 groups, as follows: i) Control (Group A); ii) ovariectomy (OVX) + hypoxia (Group B); iii) OVX + hypoxia + E2 injection (Group C); and iv) 2ME injection (Group D). The rats were maintained under hypoxic conditions for 8 weeks, and mean pulmonary artery pressure (mPAP) and pulmonary arteriole morphology were measured. The reactive oxygen species, superoxide dismutase (SOD), manganese superoxide dismutase (MnSOD), and copper-zinc superoxide dismutase (Cu/ZnSOD) levels in serum were also measured. MnSOD and HIF‑1α expression levels in lung tissue were determined by western blotting and reverse transcription‑quantitative polymerase chain reaction. The mPAP and arterial remodeling index were significantly elevated following chronic hypoxia exposure; however, experimental data revealed a reduced response in E2 and 2ME intervention rats. Compared with Group A, Group B had significantly elevated oxidative stress levels, as illustrated by increased serum ROS levels, decreased serum SOD and MnSOD levels and decreased MnSOD mRNA and protein expression levels in lung tissue. Furthermore, HIF‑1α mRNA and protein expression in Group B was significantly elevated compared with Group A. E2 and 2ME intervention significantly attenuated the aforementioned parameter changes, suggesting that E2 and 2ME partially ameliorate hypoxic pulmonary hypertension. The underlying mechanism of this may be associated with the increase in MnSOD activity and expression and reduction in ROS level, which reduces the levels of transcription and translation of HIF-1α.

View Figures

View References

1	Hoeper MM, Humbert M, Souza R, Idrees M, Kawut SM, Sliwa-Hahnle K, Jing ZC and Gibbs JS: A global view of pulmonary hypertension. Lancet Respir Med. 4:306–322. 2016. View Article : Google Scholar : PubMed/NCBI
2	Mandras SA, Gilkin RJ Jr..Pruett JA and Raspa S: Pulmonary arterial hypertension: Progress and challenges in the modern treatment era. Am J Manag Care. 20 Suppl 9:S191–S199. 2014.PubMed/NCBI
3	Weir-McCall JR, Struthers AD, Lipworth BJ and Houston JG: The role of pulmonary arterial stiffness in COPD. Respir Med. 109:1381–1390. 2015. View Article : Google Scholar : PubMed/NCBI
4	Waypa GB, Marks JD, Guzy R, Mungai PT, Schriewer J, Dokic D and Schumacker PT: Hypoxia triggers subcellular compartmental redox signaling in vascular smooth muscle cells. Circ Res. 106:526–535. 2010. View Article : Google Scholar : PubMed/NCBI
5	Schumacker PT: Lung cell hypoxia: Role of mitochondrial reactive oxygen species signaling in triggering responses. Proc Am Thorac Soc. 8:477–484. 2011. View Article : Google Scholar : PubMed/NCBI
6	Sylvester JT, Shimoda LA, Aaronson PI and Ward JP: Hypoxic pulmonary vasoconstriction. Physiol Rev. 92:367–520. 2012. View Article : Google Scholar : PubMed/NCBI
7	Al Ghouleh I, Khoo NK, Knaus UG, Griendling KK, Touyz RM, Thannickal VJ, Barchowsky A, Nauseef WM, Kelley EE, Bauer PM, et al: Oxidases and peroxidases in cardiovascular and lung disease: New concepts in reactive oxygen species signaling. Free Radic Biol Med. 51:1271–1288. 2011. View Article : Google Scholar : PubMed/NCBI
8	Vara D and Pula G: Reactive oxygen species: Physiological roles in the regulation of vascular cells. Curr Mol Med. 14:1103–1125. 2014. View Article : Google Scholar : PubMed/NCBI
9	Wang L, Zhou Y, Li M and Zhu Y: Expression of hypoxia-inducible factor-1α, endothelin-1 and adrenomedullin in newborn rats with hypoxia-induced pulmonary hypertension. Exp Ther Med. 8:335–339. 2014.PubMed/NCBI
10	Han X, Sun S, Zhao M, Cheng X, Chen G, Lin S, Guan Y and Yu X: Celastrol stimulates hypoxia-inducible factor-1 activity in tumor cells by initiating the ROS/Akt/p70S6K signaling pathway and enhancing hypoxia-inducible factor-1α protein synthesis. PLoS One. 9:e1124702014. View Article : Google Scholar : PubMed/NCBI
11	Frump AL, Goss KN, Vayl A, Albrecht M, Fisher A, Tursunova R, Fierst J, Whitson J, Cucci AR, Brown MB and Lahm T: Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: Effects of endogenous and exogenous sex hormones. Am J Physiol Lung Cell Mol Physiol. 308:L873–L890. 2015. View Article : Google Scholar : PubMed/NCBI
12	Tofovic SP, Jones T and Petrusevska G: Dose-dependent therapeutic effects of 2-Methoxyestradiol on Monocrotaline-Induced pulmonary hypertension and vascular remodeling. Prilozi. 31:279–295. 2010.PubMed/NCBI
13	Zheng Q, Yuan YD and Zhao J: Effect of estradiol and its metabolite on hypoxic induced factor-1αand alkane hydroxylase in experimental rats with ovariectomy and hypoxic pulmonary hypertension. Chinese Circulation J. 30:884–888. 2015.
14	Yuan M, Duan Z, Sun Y and Yuan Y: Effects of estrogen on ACE-AngII-AT1 axis in ovariectomy and hypoxic pulmonary hypertension rats. Zhonghua Yi Xue Za Zhi. 94:1696–1700. 2014.(In Chinese). PubMed/NCBI
15	Shen YX, Xiao K, Liang P, Ma YW and Huang X: Improvement on the modified Lowry method against interference of divalent cations in soluble protein measurement. Appl Microbiol Biotechnol. 97:4167–4178. 2013. View Article : Google Scholar : PubMed/NCBI
16	Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Sanchez MA Gomez, Kumar R Krishna, Landzberg M, Machado RF, et al: Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 62 Suppl 25:D34–D41. 2013. View Article : Google Scholar : PubMed/NCBI
17	Voelkel NF, Gomez-Arroyo J, Abbate A, Bogaard HJ and Nicolls MR: Pathobiology of pulmonary arterial hypertension and right ventricular failure. Eur Respir J. 40:1555–1565. 2012. View Article : Google Scholar : PubMed/NCBI
18	Prabhakar NR and Semenza GL: Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol Rev. 92:967–1003. 2012. View Article : Google Scholar : PubMed/NCBI
19	Abud EM, Maylor J, Undem C, Punjabi A, Zaiman AL, Myers AC, Sylvester JT, Semenza GL and Shimoda LA: Digoxin inhibits development of hypoxic pulmonary hypertension in mice. Proc Natl Acad Sci USA. 109:1239–1244. 2012. View Article : Google Scholar : PubMed/NCBI
20	Wang GL and Semenza GL: Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 270:1230–1237. 1995. View Article : Google Scholar : PubMed/NCBI
21	Semenza GL: Hypoxia-inducible factor 1: Regulator of mitochondrial metabolism and mediator of ischemic preconditioning. Biochim Biophys Acta. 1813:1263–1268. 2011. View Article : Google Scholar : PubMed/NCBI
22	Bruick RK and McKnight SL: A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 294:1337–1340. 2001. View Article : Google Scholar : PubMed/NCBI
23	Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, Dyck JR, Gomberg-Maitland M, Thébaud B, Husain AN, et al: Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: A basis for excessive cell proliferation and a new therapeutic target. Circulation. 121:2661–2671. 2010. View Article : Google Scholar : PubMed/NCBI
24	Ahmed LA, Obaid AA, Zaki HF and Agha AM: Role of oxidative stress, inflammation, nitric oxide and transforming growth factor-beta in the protective effect of diosgenin in monocrotaline-induced pulmonary hypertension in rats. Eur J Pharmacol. 740:379–387. 2014. View Article : Google Scholar : PubMed/NCBI
25	He J, Wang M, Jiang Y, Chen Q, Xu S, Xu Q, Jiang BH and Liu LZ: Chronic arsenic exposure and angiogenesis in human bronchial epithelial cells via the ROS/miR-199a-5p/HIF-1α/COX-2 pathway. Environ Health Perspect. 122:255–261. 2014.PubMed/NCBI
26	Sasabe E, Yang Z, Ohno S and Yamamoto T: Reactive oxygen species produced by the knockdown of manganese-superoxide dismutase up-regulate hypoxia-inducible factor-1alpha expression in oral squamous cell carcinoma cells. Free Radic Biol Med. 48:1321–1329. 2010. View Article : Google Scholar : PubMed/NCBI
27	Fijalkowska I, Xu W, Comhair SA, Janocha AJ, Mavrakis LA, Krishnamachary B, Zhen L, Mao T, Richter A, Erzurum SC and Tuder RM: Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells. Am J Pathol. 176:1130–1138. 2010. View Article : Google Scholar : PubMed/NCBI
28	Duracková Z: Some current insights into oxidative stress. Physiol Res. 59:459–469. 2010.PubMed/NCBI
29	Li SY, Fu ZJ and Lo AC: Hypoxia-induced oxidative stress in ischemic retinopathy. Oxid Med Cell Longev. 2012:4267692012. View Article : Google Scholar : PubMed/NCBI
30	Aggarwal S, Gross CM, Sharma S, Fineman JR and Black SM: Reactive oxygen species in pulmonary vascular remodeling. Compr Physiol. 3:1011–1034. 2013.PubMed/NCBI
31	Fukai T and Ushio-Fukai M: Superoxide dismutases: Role in redox signaling, vascular function, and diseases. Antioxid Redox Signal. 15:1583–1606. 2011. View Article : Google Scholar : PubMed/NCBI
32	Rabbani ZN, Mi J, Zhang Y, Delong M, Jackson IL, Fleckenstein K, Salahuddin FK, Zhang X, Clary B, Anscher MS and Vujaskovic Z: Hypoxia inducible factor 1alpha signaling in fractionated radiation-induced lung injury: Role of oxidative stress and tissue hypoxia. Radiat Res. 173:165–174. 2010. View Article : Google Scholar : PubMed/NCBI
33	Miyamoto N, Mandai M, Takagi H, Suzuma I, Suzuma K, Koyama S, Otani A, Oh H and Honda Y: Contrasting effect of estrogen on VEGF induction under different oxygen status and its role in murine ROP. Invest Ophthalmol Vis Sci. 43:2007–2014. 2002.PubMed/NCBI
34	Wang S, Wang B, Feng Y, Mo M, Du F, Li H and Yu X: 17β-estradiol ameliorates light-induced retinal damage in Sprague-Dawley rats by reducing oxidative stress. J Mol Neurosci. 55:141–151. 2015. View Article : Google Scholar : PubMed/NCBI
35	Liu Z, Gou Y, Zhang H, Zuo H, Zhang H, Liu Z and Yao D: Estradiol improves cardiovascular function through up-regulation of SOD2 on vascular wall. Redox Biol. 3:88–99. 2014. View Article : Google Scholar : PubMed/NCBI
36	Hagen T, D'Amico G, Quintero M, Palacios-Callender M, Hollis V, Lam F and Moncada S: Inhibition of mitochondrial respiration by the anticancer agent 2-methoxyestradiol. Biochem Biophys Res Commun. 322:923–929. 2004. View Article : Google Scholar : PubMed/NCBI
37	Ma L, Li G, Zhu H, Dong X, Zhao D, Jiang X, Li J, Qiao H, Ni S and Sun X: 2-Methoxyestradiol synergizes with sorafenib to suppress hepatocellular carcinoma by simultaneously dysregulating hypoxia-inducible factor-1 and −2. Cancer Lett. 355:96–105. 2014. View Article : Google Scholar : PubMed/NCBI
38	Verenich S and Gerk PM: Therapeutic promises of 2-methoxyestradiol and its drug disposition challenges. Mol Pharm. 7:2030–2039. 2010. View Article : Google Scholar : PubMed/NCBI
39	Basini G, Santini SE and Grasselli F: 2-Methoxyestradiol inhibits superoxide anion generation while it enhances superoxide dismutase activity in swine granulosa cells. Ann N Y Acad Sci. 1091:34–40. 2006. View Article : Google Scholar : PubMed/NCBI