eISSN: 1896-9151
ISSN: 1734-1922
Archives of Medical Science
Current issue Archive Manuscripts accepted About the journal Special issues Editorial board Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
3/2018
vol. 14
 
Share:
Share:
more
 
 
abstract:
Basic research

Overexpressed HO-1 is associated with reduced STAT3 activation in preeclampsia placenta and inhibits STAT3 phosphorylation in placental JEG-3 cells under hypoxia

Hong-Mei Qu, Li-Ping Qu, Xiao-Yan Li, Xian-Zhen Pan

Arch Med Sci 2018; 14, 3: 597–607
Online publish date: 2016/10/26
View full text
Get citation
ENW
EndNote
BIB
JabRef, Mendeley
RIS
Papers, Reference Manager, RefWorks, Zotero
AMA
APA
Chicago
Harvard
MLA
Vancouver
 
Introduction
Inadequate trophoblast invasion and placentation are widely believed to contribute to preeclampsia, and multiple lines of evidence indicate the involvement of hypoxia in preeclampsia. However, the molecular mechanisms underlying the association of placental hypoxia with preeclampsia are not clear.

Material and methods
The present study focused on the role in preeclampsia of heme oxygenase 1 (HO-1), which is an inducible isoform of HO in response to hypoxia, via examining the expression of HO-1 and the expression and phosphorylation (Tyr705) of Signal transducer and activator of transcription (STAT) 3 in preeclamptic placentas via the immunohistochemical method, western blotting assay and RT-qPCR method. Then we investigated the regulation by HO-1 of the expression and phosphorylation of STAT3 in human placental choriocarcinoma JEG-3 cells under hypoxia.

Results
There was upregulation of HO-1 at both mRNA (1.506 ±0.08347 (N = 37) vs. 1.000 ±0.08854 (N = 31), p < 0.0001) and protein (0.630 ±0.155 (N = 35) vs. 0.310 ±0.052, 0.630 ±0.155 (N = 35), p < 0.001) levels and a reduced level of STAT3 phosphorylation (Tyr 705) in the preeclamptic placental tissues, compared to normal placental tissues (0.143 ±0.027 (N = 35) vs. 0.194 ±0.028 (N = 35), p < 0.01). Also, in vitro experiments demonstrated that HO-1 was markedly promoted by hypoxia in human placental choriocarcinoma JEG-3 cells, 6 or 12 h post treatment (p < 0.05 or p < 0.01). However, the STAT3 phosphorylation (Tyr 705) was attenuated by sustained hypoxia (p < 0.01). Moreover, it was demonstrated that HO-1 overexpression significantly inhibited the hypoxia-promoted STAT3 phosphorylation (Tyr 705).

Conclusions
HO-1 was overexpressed in PE placenta, in association with reduced STAT3 phosphorylation (Tyr 705). HO-1 inhibits the STAT3 phosphorylation in placental JEG-3 cells under hypoxia. Thus, we speculate that overexpressed HO-1 might contribute to the reduced STAT3 phosphorylation (Tyr 705) and the pathogenesis of preeclampsia.

keywords:

heme oxygenase 1, STAT3 phosphorylation (Tyr 705), hypoxia, preeclampsia

references:
Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009; 33: 130-7.
Steegers EA, von Dadelszen P, Duvekot JJ, et al. Pre-eclampsia. Lancet 2010; 376: 631-44.
Ghulmiyyah L, Sibai B. Maternal mortality from preeclampsia/eclampsia. Semin Perinatol 2012; 36: 56-9.
Red-Horse K, Zhou Y, Genbacev O, et al. Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. J Clin Invest 2004; 114: 744-54.
Genbacev O, Zhou Y, Ludlow JW, et al. Regulation of human placental development by oxygen tension. Science 1997; 277: 1669-72.
Davison JM, Homuth V, Jeyabalan A, et al. New aspects in the pathophysiology of preeclampsia. J Am Soc Nephrol 2004; 15: 2440-8.
DiFederico E, Genbacev O, Fisher SJ. Preeclampsia is associated with widespread apoptosis of placental cytotrophoblasts within the uterine wall. Am J Pathol 1999; 155: 293-301.
Ishihara N, Matsuo H, Murakoshi H, et al. Increased apoptosis in the syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation. Am J Obstet Gynecol 2002; 186: 158-66.
Crocker IP, Cooper S, Ong SC, et al. Differences in apoptotic susceptibility of cytotrophoblasts and syncytiotrophoblasts in normal pregnancy to those complicated with preeclampsia and intrauterine growth restriction. Am J Pathol 2003; 162: 637-43.
Hu C, Smith SD, Pang L, et al. Enhanced basal apoptosis in cultured term human cytotrophoblasts is associated with a higher expression and physical interaction of p53 and Bak. Placenta 2006; 27: 978-83.
Lunell NO, Nylund LE, Lewander R, et al. Uteroplacental blood flow in pre-eclampsia measurements with indium-113m and a computer-linked gamma camera. Clin Exp Hypertens B 1982; 1: 105-17.
Zamudio S, Wu Y, Ietta F, et al. Human placental hypoxia-inducible factor-1alpha expression correlates with clinical outcomes in chronic hypoxia in vivo. Am J Pathol 2007; 170: 2171-9.
Soleymanlou N, Jurisica I, Nevo O, et al. Molecular evidence of placental hypoxia in preeclampsia. J Clin Endocrinol Metab 2005; 90: 4299-308.
Gilbert J, Dukes M, LaMarca B, et al. Effects of reduced uterine perfusion pressure on blood pressure and metabolic factors in pregnant rats. Am J Hypertens 2007; 20: 686-91.
Makris A, Thornton C, Thompson J, et al. Uteroplacental ischemia results in proteinuric hypertension and elevated sFLT-1. Kidney Int 2007; 71: 977-84.
Meekins JW, Pijnenborg R, Hanssens M, et al. A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies. Br J Obstet Gynaecol 1994; 101: 669-74.
Onogi A, Naruse K, Sado T, et al. Hypoxia inhibits invasion of extravillous trophoblast cells through reduction of matrix metalloproteinase (MMP)-2 activation in the early first trimester of human pregnancy. Placenta 2011; 32: 665-70.
Fitzgerald JS, Poehlmann TG, Schleussner E, et al. Trophoblast invasion: the role of intracellular cytokine signalling via signal transducer and activator of transcription 3 (STAT3). Hum Reprod Update 2008; 14: 335-44.
Garcia MG, Tirado-Gonzalez I, Handjiski B, et al. High expression of survivin and down-regulation of Stat-3 characterize the feto-maternal interface in failing murine pregnancies during the implantation period. Placenta 2007; 28: 650-7.
Li CF, Gou WL, Li XL, et al. Reduced expression of survivin, the inhibitor of apoptosis protein correlates with severity of preeclampsia. Placenta 2012; 33: 47-51.
Xie TX, Wei D, Liu M, et al. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene 2004; 23: 3550-60.
Takeda K, Noguchi K, Shi W, et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci U S A 1997; 94: 3801-04.
Zhang Z, Yang X, Zhang L, et al. Decreased expression and activation of Stat3 in severe preeclampsia. J Mol Histol 2015; 46: 205-19.
Hirano T, Ishihara K, Hibi M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 2000; 19: 2548-56.
Huang WL, Yeh HH, Lin CC, et al. Signal transducer and activator of transcription 3 activation up-regulates interleukin-6 autocrine production: a biochemical and genetic study of established cancer cell lines and clinical isolated human cancer cells. Mol Cancer 2010; 9: 309.
Artunc-Ulkumen B, Guvenc Y, Goker A, et al. Maternal Serum S100-B, PAPP-A and IL-6 levels in severe preeclampsia. Arch Gynecol Obstet 2015; 292: 97-102.
Chen Q, Zhao M, Guo F, et al. The reduction of circulating levels of IL-6 in pregnant women with preeclampsia by magnesium sulphate and nifedipine: in vitro evidence for potential mechanisms. Placenta 2015; 36: 661-6.
Mihu D, Razvan C, Malutan A, et al. Evaluation of maternal systemic inflammatory response in preeclampsia. Taiwan J Obstet Gynecol 2015; 54: 160-6.
Udenze I, Amadi C, Awolola N, et al. The role of cytokines as inflammatory mediators in preeclampsia. Pan Afr Med J 2015; 20: 219.
Rahardjo B, Widjajanto E, Sujuti H, et al. Different levels of IL-1alpha, IL-6, TNF-alpha, NF-kappaB and PPAR-gamma in monocyte cultures exposed by plasma preeclampsia and normotensive pregnancy. Pregnancy Hypertens 2014; 4: 187-93.
Ryter SW, Alam J, Choi AM. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 2006; 86: 583-650.
Seck K, Fischer T. Diagnosis and treatment of preeclampsia: overview of international recommendations. Z Geburtshilfe Neonatol 2009; 213: 106-12.
Iriyama T, Wang W, Parchim NF, et al. Hypoxia-independent upregulation of placental hypoxia inducible factor-1alpha gene expression contributes to the pathogenesis of preeclampsia. Hypertension 2015; 65: 1307-15.
Bosco C, Diaz E, Gutierrez R, et al. Placental hypoxia developed during preeclampsia induces telocytes apoptosis in chorionic villi affecting the maternal-fetus metabolic exchange. Curr Stem Cell Res Ther 2016; 11: 420-5.
Zhang Y, Zhang L, Wu J, et al. Heme oxygenase-1 exerts a protective role in ovalbumin-induced neutrophilic airway inflammation by inhibiting Th17 cell-mediated immune response. J Biol Chem 2013; 288: 34612-26.
Yang YC, Huang YT, Hsieh CW, et al. Carbon monoxide induces heme oxygenase-1 to modulate STAT3 activation in endothelial cells via S-glutathionylation. Plos One 2014; 9: e100677.
Jauniaux E, Burton GJ. Pathophysiology of histological changes in early pregnancy loss. Placenta 2005; 26: 114-23.
Norwitz ER. Defective implantation and placentation: laying the blueprint for pregnancy complications. Reprod Biomed Online 2006; 13: 591-9.
Muntener M, Hsu YC. Development of trophoblast and placenta of the mouse. A reinvestigation with regard to the in vitro culture of mouse trophoblast and placenta. Acta Anat (Basel) 1977; 98: 241-52.
Enders AC, Welsh AO. Structural interactions of trophoblast and uterus during hemochorial placenta formation. J Exp Zool 1993; 266: 578-87.
Fitzgerald JS, Busch S, Wengenmayer T, et al. Signal transduction in trophoblast invasion. Chem Immunol Allergy 2005; 88: 181-99.
Darnell JJ. Phosphotyrosine signaling and the single cell: metazoan boundary. Proc Natl Acad Sci U S A 1997; 94: 11767-9.
Poehlmann TG, Fitzgerald JS, Meissner A, et al. Trophoblast invasion: tuning through LIF, signalling via Stat3. Placenta 2005; 26 Suppl A: S37-41.
Qu HM, Mu LS, Liu HJ, Wang XT. Hypoxia exacerbates the impairment of PIGF/JAK-STAT3 signaling and drug metabolizing enzymes in preeclampsia. Lat Am J Pharm 2016; 35: 17-25.
Zhao R, Feng J, He G. Hypoxia increases Nrf2-induced HO-1 expression via the PI3K/Akt pathway. Front Biosci (Landmark Ed) 2016; 21: 385-96.
Kweider N, Fragoulis A, Rosen C, et al. Interplay between vascular endothelial growth factor (VEGF) and nuclear factor erythroid 2-related factor-2 (Nrf2): implications for preeclampsia. J Biol Chem 2011; 286: 42863-72.
Han Q, Yeung SC, Ip MS, et al. Intermittent hypoxia-induced NF-kappaB and HO-1 regulation in human endothelial EA.hy926 cells. Cell Biochem Biophys 2013; 66: 431-41.
Kweider N, Fragoulis A, Rosen C, et al. Interplay between vascular endothelial growth factor (VEGF) and nuclear factor erythroid 2-related factor-2 (Nrf2): implications for preeclampsia. J Biol Chem 2011; 286: 42863-72.
Chigusa Y, Tatsumi K, Kondoh E, et al. 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: E1862-70.
Tong S, Kaitu’U-Lino TJ, Onda K, et al. Heme oxygenase-1 is not decreased in preeclamptic placenta and does not negatively regulate placental soluble fms-like tyrosine kinase-1 or soluble endoglin secretion. Hypertension 2015; 66: 1073-81.
FEATURED PRODUCTS
Quick links
© 2018 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe