Inhibitory effects of 17β-estradiol or a resveratrol dimer on hypoxia-inducible factor-1α in genioglossus myoblasts: Involvement of ERα and its downstream p38 MAPK pathways

Li,Yuanyuan; Liu,Yuehua; Lu,Yun; Zhao,Bingjiao

doi:10.3892/ijmm.2017.3123

Inhibitory effects of 17β-estradiol or a resveratrol dimer on hypoxia-inducible factor-1α in genioglossus myoblasts: Involvement of ERα and its downstream p38 MAPK pathways

Authors:
- Yuanyuan Li
- Yuehua Liu
- Yun Lu
- Bingjiao Zhao
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Affiliations: Department of Orthodontics, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai 200072, P.R. China, Department of Orthodontics, Shanghai Stomatological Hospital, Shanghai 200001, P.R. China
Published online on: September 7, 2017 https://doi.org/10.3892/ijmm.2017.3123
Pages: 1347-1356
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Deficiency in the functioning of the genioglossus, which is one of the upper airway dilator muscles, is an important cause of obstructive sleep apnea/hypopnea syndrome (OSAHS). Estrogens have been reported to inhibit hypoxia-inducible factor-1α (HIF-1α) expression in hypoxia, regulating its target genes and exerting protective effects on the genioglossus in chronic intermittent hypoxia (CIH). This study aimed to investigate the role of 17β-estradiol (E2) and a resveratrol dimer (RD) on HIF-1α and the underlying mechanism. Mouse genioglossus myoblasts were isolated and cultured, and the estrogen receptor α (ERα) shRNA lentivirus was used for gene knockdown. Then MTT assay was used to determine the effects of E2 and RD on the viability of the cells. Cells in different groups were treated with different agents (E2, or RD, or E2 and SB203580), incubated under normoxia or hypoxia for 24 h, and then expression levels of HIF-1α, ERα, ERβ, total-p38 MAPK and phospho-p38 MAPK were detected. We observed that both E2 and RD inhibited the overexpression of HIF-1α induced by hypoxia at the mRNA and protein levels, and these effects were eliminated by genetic silencing of ERα by RNAi. In addition, we found that E2 activated p38 MAPK pathways to inhibit HIF-1α expression. On the whole, ERα may be responsible for downregulation of HIF-1α by E2 or RD via activation of downstream p38 MAPK pathways.

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1	Eckert DJ and Malhotra A: Pathophysiology of adult obstructive sleep apnea. Proc Am Thorac Soc. 5:144–153. 2008. View Article : Google Scholar : PubMed/NCBI
2	Douglas NJ and Polo O: Pathogenesis of obstructive sleep apnoea/hypopnoea syndrome. Lancet. 344:653–655. 1994. View Article : Google Scholar : PubMed/NCBI
3	Owens RL, Eckert DJ, Yeh SY and Malhotra A: Upper airway function in the pathogenesis of obstructive sleep apnea: A review of the current literature. Curr Opin Pulm Med. 14:519–524. 2008. View Article : Google Scholar : PubMed/NCBI
4	Sériès FJ, Simoneau SA, Pierre S St and Marc I: Characteristics of the genioglossus and musculus uvulae in sleep apnea hypopnea syndrome and in snorers. Am J Respir Crit Care Med. 153:1870–1874. 1996. View Article : Google Scholar : PubMed/NCBI
5	Bradford A, McGuire M and O'Halloran KD: Does episodic hypoxia affect upper airway dilator muscle function? Implications for the pathophysiology of obstructive sleep apnoea. Respir Physiol Neurobiol. 147:223–234. 2005. View Article : Google Scholar : PubMed/NCBI
6	Malhotra A, Pillar G, Fogel RB, Beauregard J, Edwards JK, Slamowitz DI, Shea SA and White DP: Genioglossal but not palatal muscle activity relates closely to pharyngeal pressure. Am J Respir Crit Care Med. 162:1058–1062. 2000. View Article : Google Scholar : PubMed/NCBI
7	Cai Z, Manalo DJ, Wei G, Rodriguez ER, Fox-Talbot K, Lu H, Zweier JL and Semenza GL: Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Cir culation. 108:79–85. 2003.
8	Yuan G, Nanduri J, Bhasker CR, Semenza GL and Prabhakar NR: Ca²⁺/calmodulin kinase-dependent activation of hypoxia inducible factor 1 transcriptional activity in cells subjected to intermittent hypoxia. J Biol Chem. 280:4321–4328. 2005. View Article : Google Scholar
9	Pae EK, Wu J, Nguyen D, Monti R and Harper RM: Geniohyoid muscle properties and myosin heavy chain composition are altered after short-term intermittent hypoxic exposure. J Appl Physiol (1985). 98:889–894. 2005. View Article : Google Scholar
10	Chen L, Zhang J, Gan TX, Chen-Izu Y, Hasday JD, Karmazyn M, Balke CW and Scharf SM: Left ventricular dysfunction and associated cellular injury in rats exposed to chronic intermittent hypoxia. J Appl Physiol (1985). 104:218–223. 2008. View Article : Google Scholar
11	Stroka DM, Burkhardt T, Desbaillets I, Wenger RH, Neil DA, Bauer C, Gassmann M and Candinas D: HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia. FASEB J. 15:2445–2453. 2001.PubMed/NCBI
12	Zhou J and Liu Y: Effects of genistein and estrogen on the genioglossus in rats exposed to chronic intermittent hypoxia may be HIF-1α dependent. Oral Dis. 19:702–711. 2013. View Article : Google Scholar : PubMed/NCBI
13	Jia SS and Liu YH: Down-regulation of hypoxia inducible factor-1 alpha: A possible explanation for the protective effects of estrogen on genioglossus fatigue resistance. Eur J Oral Sci. 118:139–144. 2010. View Article : Google Scholar : PubMed/NCBI
14	Lu Y, Liu Y and Li Y: Comparison of natural estrogens and synthetic derivative on genioglossus function and estrogen receptors expression in rats with chronic intermittent hypoxia. J Steroid Biochem Mol Biol. 140:71–79. 2014. View Article : Google Scholar
15	Solakidi S, Psarra AM and Sekeris CE: Differential distribution of glucocorticoid and estrogen receptor isoforms: Localization of GRbeta and ERalpha in nucleoli and GRalpha and ERbeta in the mitochondria of human osteosarcoma SaOS-2 and hepatocarcinoma HepG2 cell lines. J Musculoskelet Neuronal Interact. 7:240–245. 2007.PubMed/NCBI
16	Aschim EL, Saether T, Wiger R, Grotmol T and Haugen TB: Differential distribution of splice variants of estrogen receptor beta in human testicular cells suggests specific functions in spermatogenesis. J Steroid Biochem Mol Biol. 92:97–106. 2004. View Article : Google Scholar : PubMed/NCBI
17	Couse JF, Lindzey J, Grandien K, Gustafsson JA and Korach KS: Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse. Endocrinology. 138:4613–4621. 1997. View Article : Google Scholar : PubMed/NCBI
18	Kalbe C, Mau M, Wollenhaupt K and Rehfeldt C: Evidence for estrogen receptor alpha and beta expression in skeletal muscle of pigs. Histochem Cell Biol. 127:95–107. 2007. View Article : Google Scholar
19	Veasey SC, Guilleminault C, Strohl KP, Sanders MH, Ballard RD and Magalang UJ: Medical therapy for obstructive sleep apnea: A review by the Medical Therapy for Obstructive Sleep Apnea Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 29:1036–1044. 2006. View Article : Google Scholar : PubMed/NCBI
20	Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Rein J, Vela-Bueno A and Kales A: Prevalence of sleep-disordered breathing in women: Effects of gender. Am J Respir Crit Care Med. 163:608–613. 2001. View Article : Google Scholar : PubMed/NCBI
21	Pickett CK, Regensteiner JG, Woodard WD, Hagerman DD, Weil JV and Moore LG: Progestin and estrogen reduce sleep-disordered breathing in postmenopausal women. J Appl Physiol (1985). 66:1656–1661. 1989.
22	Popovic RM and White DP: Upper airway muscle activity in normal women: Influence of hormonal status. J Appl Physiol (1985). 84:1055–1062. 1998.
23	Patisaul HB and Jefferson W: The pros and cons of phytoestrogens. Front Neuroendocrinol. 31:400–419. 2010. View Article : Google Scholar : PubMed/NCBI
24	Zhong C, Zhu J, Chang J and Sun X: Concise total syntheses of (±)isopaucifloral F, (±)quadrangularin A, and (±)pallidol. Tetrahedron Lett. 52:2815–2817. 2011. View Article : Google Scholar
25	Bi R, Broutman G, Foy MR, Thompson RF and Baudry M: The tyrosine kinase and mitogen-activated protein kinase pathways mediate multiple effects of estrogen in hippocampus. Proc Natl Acad Sci USA. 97:3602–3607. 2000. View Article : Google Scholar : PubMed/NCBI
26	Song RX, McPherson RA, Adam L, Bao Y, Shupnik M, Kumar R and Santen RJ: Linkage of rapid estrogen action to MAPK activation by ERalpha-Shc association and Shc pathway activation. Mol Endocrinol. 16:116–127. 2002.PubMed/NCBI
27	Chen CC, Lee WR and Safe S: Egr-1 is activated by 17beta-estradiol in MCF-7 cells by mitogen-activated protein kinase-dependent phosphorylation of ELK-1. J Cell Biochem. 93:1063–1074. 2004. View Article : Google Scholar : PubMed/NCBI
28	Kazi AA and Koos RD: Estrogen-induced activation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor expression, and edema in the uterus are mediated by the phosphatidylinositol 3-kinase/Akt pathway. Endocrinology. 148:2363–2374. 2007. View Article : Google Scholar : PubMed/NCBI
29	Yun SP, Lee MY, Ryu JM, Song CH and Han HJ: Role of HIF-1alpha and VEGF in human mesenchymal stem cell proliferation by 17beta-estradiol: Involvement of PKC, PI3K/Akt, and MAPKs. Am J Physiol Cell Physiol. 296:C317–C326. 2009. View Article : Google Scholar
30	Hou YX, Jia SS and Liu YH: 17beta-Estradiol accentuates contractility of rat genioglossal muscle via regulation of estrogen receptor alpha. Arch Oral Biol. 55:309–317. 2010. View Article : Google Scholar : PubMed/NCBI
31	Xu J, Xiang Q, Lin G, Fu X, Zhou K, Jiang P, Zheng S and Wang T: Estrogen improved metabolic syndrome through down-regulation of VEGF and HIF-1α to inhibit hypoxia of periaortic and intra-abdominal fat in ovariectomized female rats. Mol Biol Rep. 39:8177–8185. 2012. View Article : Google Scholar : PubMed/NCBI
32	Miyauchi Y, Sato Y, Kobayashi T, Yoshida S, Mori T, Kanagawa H, Katsuyama E, Fujie A, Hao W, Miyamoto K, et al: HIF1α is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis. Proc Natl Acad Sci USA. 110:16568–16573. 2013. View Article : Google Scholar
33	Rzemieniec J, Litwa E, Wnuk A, Lason W, Gołas A, Krzeptowski W and Kajta M: Neuroprotective action of raloxifene against hypoxia-induced damage in mouse hippocampal cells depends on ERα but not ERβ or GPR30 signalling. J Steroid Biochem Mol Biol. 146:26–37. 2015. View Article : Google Scholar
34	Camps C, Saini HK, Mole DR, Choudhry H, Reczko M, Guerra-Assunção JA, Tian YM, Buffa FM, Harris AL, Hatzigeorgiou AG, et al: Integrated analysis of microRNA and mRNA expression and association with HIF binding reveals the complexity of microRNA expression regulation under hypoxia. Mol Cancer. 13:282014. View Article : Google Scholar : PubMed/NCBI
35	Chung HY, Lee SJ, Lee JM, Huh S, Kim HK, Kwon OH, Lim HJ, Oh EJ, Kim TJ, O TM, et al: Expression patterns of HIF-1alpha under hypoxia in vascular smooth muscle cells of venous malformations. Ann Plast Surg. 75:332–7. 2015. View Article : Google Scholar
36	Yi P, Driscoll MD, Huang J, Bhagat S, Hilf R, Bambara RA and Muyan M: The effects of estrogen-responsive element- and ligand-induced structural changes on the recruitment of cofactors and transcriptional responses by ER alpha and ER beta. Mol Endocrinol. 16:674–693. 2002.PubMed/NCBI
37	Filardo EJ, Quinn JA, Bland KI and Frackelton AR Jr: Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol. 14:1649–1660. 2000. View Article : Google Scholar : PubMed/NCBI
38	Thomas P, Pang Y, Filardo EJ and Dong J: Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology. 146:624–632. 2005. View Article : Google Scholar
39	Revankar CM, Cimino DF, Sklar LA, Arterburn JB and Prossnitz ER: A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 307:1625–1630. 2005. View Article : Google Scholar : PubMed/NCBI
40	De Francesco EM, Pellegrino M, Santolla MF, Lappano R, Ricchio E, Abonante S and Maggiolini M: GPER mediates activation of HIF1α/VEGF signaling by estrogens. Cancer Res. 74:4053–4064. 2014. View Article : Google Scholar : PubMed/NCBI
41	Guzeloglu Kayisli O, Kayisli UA, Luleci G and Arici A: In vivo and in vitro regulation of Akt activation in human endometrial cells is estrogen dependent. Biol Reprod. 71:714–721. 2004. View Article : Google Scholar : PubMed/NCBI
42	Linford NJ, Yang Y, Cook DG and Dorsa DM: Neuronal apoptosis resulting from high doses of the isoflavone genistein: Role for calcium and p42/44 mitogen-activated protein kinase. J Pharmacol Exp Ther. 299:67–75. 2001.PubMed/NCBI
43	Salceda S, Beck I, Srinivas V and Caro J: Complex role of protein phosphorylation in gene activation by hypoxia. Kidney Int. 51:556–559. 1997. View Article : Google Scholar : PubMed/NCBI
44	Mazure NM, Chen EY, Laderoute KR and Giaccia AJ: Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood. 90:3322–3331. 1997.PubMed/NCBI