Background: Previous studies have shown that oxidative stress is an important factor in preeclampsia (PE). Heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor-2 (Nrf2) are protective proteins that are involved in combating oxidative stress in the body. Nrf2 is also an essential upstream transcription factor regulating HO-1. This study was aimed at exploring the physiological roles of HO-1 and Nrf2 in PE. Methods: Serum and placenta were collected from 30 patients who presented with severe PE and 30 healthy pregnant females. HO-1 and Nrf2 levels in placenta were measured. Following stimulation of the HTR-8/SVneo cell line with tert-butylhydroquinone (tBHQ), an Nrf2 activator, nuclear Nrf2 protein and HO-1 mRNA levels were determined. Results: Compared with the healthy pregnancy group, HO-1 protein and mRNA levels were increased in placental samples obtained from the severe PE group (p < 0.01, p < 0.05). Similar increases were also observed for Nrf2 protein levels (p < 0.01). Nuclear Nrf2 protein and HO-1 mRNA levels were both increased in the HTR-8/SVneo cell line following stimulation with tBHQ (p < 0.05). Conclusion: Patients with severe PE may be protected against oxidative injury following an elevation in HO-1 and Nrf2 levels. Nrf2 is likely to have a synergistic effect on HO-1 in PE.

1.
Zhang Y, Ye Y, Wang Y, Chen W: Inhibition of lectin-like oxidized low-density lipoprotein receptor 1 protects against plasma/hypoxia-mediated trophoblast dysfunction associated with preeclampsia. Gynecol Obstet Invest 2015;79:90-96.
2.
Choi BM, Pae HO, Jeong YR, Oh GS, Jun CD, Kim BR, Kim YM, Chung HT: Overexpression of heme oxygenase (HO)-1 renders Jurkat T cells resistant to fas-mediated apoptosis: involvement of iron released by HO-1. Free Radic Biol Med 2004;36:858-871.
3.
Abraham NG, Kappas A: Heme oxygenase and the cardiovascular-renal system. Free Radic Biol Med 2005;39:1-25.
4.
Zhao S, Zhang Y, Gu Y, Lewis DF, Wang Y: Heme oxygenase-1 mediates up-regulation of adhesion molecule expression induced by peroxynitrite in endothelial cells. J Soc Gynecol Investig 2004;11:465-471.
5.
Acevedo CH, Ahmed A: Hemeoxygenase-1 inhibits human myometrial contractility via carbon monoxide and is upregulated by progesterone during pregnancy. J Clin Invest 1998;101:949-955.
6.
Zhao H, Azuma J, Kalish F, Wong RJ, Stevenson DK: Maternal heme oxygenase 1 regulates placental vasculature development via angiogenic factors in mice. Biol Reprod 2011;85:1005-1012.
7.
Zhao H, Wong RJ, Kalish FS, Nayak NR, Stevenson DK: Effect of heme oxygenase-1 deficiency on placental development. Placenta 2009;30:861-868.
8.
Eide IP, Isaksen CV, Salvesen KA, Langaas M, Schønberg SA, Austgulen R: Decidual expression and maternal serum levels of heme oxygenase 1 are increased in pre-eclampsia. Acta Obstet Gynecol Scand 2008;87:272-279.
9.
Vitoratos N, Papakonstantinou K, Deliveliotou A, Economou E, Panoulis C, Hassiakos D, Creatsas GK: Antepartum and postpartum serum heme oxygenase-1 levels in preeclamptic and normotensive pregnant women. In Vivo 2011;25:445-450.
10.
Nakamura M, Sekizawa A, Purwosunu Y, Okazaki S, Farina A, Wibowo N, Shimizu H, Okai T: Cellular mRNA expressions of anti-oxidant factors in the blood of preeclamptic women. Prenat Diagn 2009;29:691-696.
11.
McCaig D, Lyall F: Heme oxygenase expression in human placental villous tissue in response to exposure to in vitro ischemia-reperfusion injury. Hypertens Pregnancy 2009;28:256-272.
12.
Zenclussen AC, Lim E, Knoeller S, Knackstedt M, Hertwig K, Hagen E, Klapp BF, Arck PC: Heme oxygenases in pregnancy II: HO-2 is downregulated in human pathologic pregnancies. Am J Reprod Immunol 2003;50:66-76.
13.
Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y: An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 1997;236:313-322.
14.
Lee JM, Li J, Johnson DA, Stein TD, Kraft AD, Calkins MJ, Jakel RJ, Johnson JA: Nrf2, a multi-organ protector? FASEB J 2005;19:1061-1066.
15.
Chigusa Y, Tatsumi K, Kondoh E, Fujita K, Nishimura F, Mogami H, Konishi I: Decreased lectin-like oxidized LDL receptor 1 (LOX-1) and low Nrf2 activation in placenta are involved in preeclampsia. J Clin Endocrinol Metab 2012;97:E1862-E1870.
16.
Kweider N, Huppertz B, Wruck CJ, Beckmann R, Rath W, Pufe T, Kadyrov M: A role for Nrf2 in redox signalling of the invasive extravillous trophoblast in severe early onset IUGR associated with preeclampsia. PLoS One 2012;7:e47055.
17.
Løset M, Mundal SB, Johnson MP, Fenstad MH, Freed KA, Lian IA, Eide IP, Bjørge L, Blangero J, Moses EK, Austgulen R: A transcriptional profile of the decidua in preeclampsia. Am J Obstet Gynecol 2011;204:84.e81-e27.
18.
Ishii T, Itoh K, Ruiz E, Leake DS, Unoki H, Yamamoto M, Mann GE: Role of Nrf2 in the regulation of CD36 and stress protein expression in murine macrophages: activation by oxidatively modified LDL and 4-hydroxynonenal. Circ Res 2004;94:609-616.
19.
Graham CH, Hawley TS, Hawley RG, MacDougall JR, Kerbel RS, Khoo N, Lala PK: Establishment and characterization of first trimester human trophoblast cells with extended lifespan. Exp Cell Res 1993;206:204-211.
20.
Arlt A, Sebens S, Krebs S, Geismann C, Grossmann M, Kruse ML, Schreiber S, Schäfer H: Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene 2013;32:4825-4835.
21.
Barber A, Robson SC, Myatt L, Bulmer JN, Lyall F: Heme oxygenase expression in human placenta and placental bed: reduced expression of placenta endothelial HO-2 in preeclampsia and fetal growth restriction. FASEB J 2001;15:1158-1168.
22.
McLaughlin BE, Lash GE, Smith GN, Marks GS, Nakatsu K, Graham CH, Brien JF: Heme oxygenase expression in selected regions of term human placenta. Exp Biol Med (Maywood) 2003;228:564-567.
23.
Erdemli HK, Yildirimlar P, Alper TY, Kocabaş R, Salis O, Bedir A: Increased serum heme oxygenase-1 levels as a diagnostic marker of oxidative stress in preeclampsia. Hypertens Pregnancy 2014;33:1-10.
24.
Zhong JL, Raval CM, Nisar MF, Bian C, Zhang J, Yang L, Tyrrell RM: Development of refractoriness of HO-1 induction to a second treatment with UVA radiation and the involvement of Nrf2 in human skin fibroblasts. Photochem Photobiol 2014;90:1340-1348.
25.
Yang CM, Lin CC, Lee IT, Hsu CK, Tai YC, Hsieh HL, Chi PL, Hsiao LD: c-Src-dependent transactivation of EGFR mediates CORM-2-induced HO-1 expression in human tracheal smooth muscle cells. J Cell Physiol 2015;230:2351-2361.
26.
Askenazi DJ, Halloran B, Patil N, Keeling S, Saeidi B, Koralkar R, Ambalavanan N: Genetic polymorphisms of heme-oxygenase 1 (HO-1) may impact on acute kidney injury, bronchopulmonary dysplasia, and mortality in premature infants. Pediatr Res 2015;77:793-798.
27.
Yang M, Kimura M, Ng C, He J, Keshvari S, Rose FJ, Barclay JL, Whitehead JP: Induction of heme-oxygenase-1 (HO-1) does not enhance adiponectin production in human adipocytes: evidence against a direct HO-1 - adiponectin axis. Mol Cell Endocrinol 2015;413:209-216.
28.
Mylroie H, Dumont O, Bauer A, Thornton CC, Mackey J, Calay D, Hamdulay SS, Choo JR, Boyle JJ, Samarel AM, Randi AM, Evans PC, Mason JC: PKCε-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis. Cardiovasc Res 2015;106:509-519.
29.
Ma D, Fang Q, Wang P, Gao R, Sun J, Li Y, Hu XY, Wang JS: Downregulation of HO-1 promoted apoptosis induced by decitabine via increasing p15INK4B promoter demethylation in myelodysplastic syndrome. Gene Ther 2015;22:287-296.
30.
Liu C, Zhu C, Wang G, Xu R, Zhu Y: Higenamine regulates Nrf2-HO-1-Hmgb1 axis and attenuates intestinal ischemia-reperfusion injury in mice. Inflamm Res 2015;64:395-403.
31.
Detsika MG, Duann P, Lianos EA: HO-1 expression control in the rat glomerulus. Biochem Biophys Res Commun 2015;460:786-792.
32.
Fetoni AR, Paciello F, Rolesi R, Eramo SL, Mancuso C, Troiani D, Paludetti G: Rosmarinic acid up-regulates the noise-activated Nrf2/HO-1 pathway and protects against noise-induced injury in rat cochlea. Free Radic Biol Med 2015;85:269-281.
33.
Lee IT, Wang SW, Lee CW, Chang CC, Lin CC, Luo SF, Yang CM: Lipoteichoic acid induces HO-1 expression via the TLR2/MyD88/c-Src/NADPH oxidase pathway and Nrf2 in human tracheal smooth muscle cells. J Immunol 2008;181:5098-5110.
34.
Iuchi T, Akaike M, Mitsui T, Ohshima Y, Shintani Y, Azuma H, Matsumoto T: Glucocorticoid excess induces superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction. Circ Res 2003;92:81-87.
35.
You JM, Yun SJ, Nam KN, Kang C, Won R, Lee EH: Mechanism of glucocorticoid-induced oxidative stress in rat hippocampal slice cultures. Can J Physiol Pharmacol 2009;87:440-447.
36.
Yamagishi S, Nakamura K, Matsui T: Role of oxidative stress in the development of vascular injury and its therapeutic intervention by nifedipine. Curr Med Chem 2008;15:172-177.
37.
Allanore Y, Borderie D, Lemaréchal H, Ekindjian OG, Kahan A: Acute and sustained effects of dihydropyridine-type calcium channel antagonists on oxidative stress in systemic sclerosis. Am J Med 2004;116:595-600.
38.
Chander V, Chopra K: Nifedipine attenuates changes in nitric oxide levels, renal oxidative stress, and nephrotoxicity induced by cyclosporine. Ren Fail 2005;27:441-450.
39.
Allanore Y, Borderie D, Lemaréchal H, Ekindjian OG, Kahan A: Nifedipine decreases sVCAM-1 concentrations and oxidative stress in systemic sclerosis but does not affect the concentrations of vascular endothelial growth factor or its soluble receptor 1. Arthritis Res Ther 2004;6:R309-R314.
40.
Ma Q: Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 2013;53:401-426.
41.
Singh S, Vrishni S, Singh BK, Rahman I, Kakkar P: Nrf2-ARE stress response mechanism: a control point in oxidative stress-mediated dysfunctions and chronic inflammatory diseases. Free Radic Res 2010;44:1267-1288.
42.
Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, Yamamoto M: Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem 2000;275:16023-16029.
43.
Wruck CJ, Huppertz B, Bose P, Brandenburg LO, Pufe T, Kadyrov M: Role of a fetal defence mechanism against oxidative stress in the aetiology of preeclampsia. Histopathology 2009;55:102-106.
44.
Acar N, Soylu H, Edizer I, Ozbey O, Er H, Akkoyunlu G, Gemici B, Ustunel I: Expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxiredoxin 6 (Prdx6) proteins in healthy and pathologic placentas of human and rat. Acta Histochem 2014;116:1289-1300.
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