Skip to main content

Advertisement

Log in

Gadd45α as an upstream signaling molecule of p38 MAPK triggers oxidative stress-induced sFlt-1 and sEng upregulation in preeclampsia

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Preeclampsia (PE) is known to be associated with increased circulating levels of anti-angiogenic factors, such as soluble fms-related tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). However, the way that placental oxidative stress results in the elevation of these two factors remains enigmatic. We have observed the overexpression of growth arrest and DNA damage-inducible 45 alpha (Gadd45α) and excessive activation of p38 mitogen-activated protein kinase (MAPK) in preeclamptic placentas compared with normotensive controls, together with increased levels of sFlt-1 and sEng in maternal sera in patients with PE. Moreover, Gadd45α knockdown or p38 inhibition provides protective effects in hypoxia/reoxygenation (H/R)-exposed human umbilical vein endothelial cells (HUVECs) by suppressing oxidative stress, inhibiting apoptosis, and promoting their potential for in vitro angiogenesis. A regulatory signaling pathway in which H/R intervention causes the induction of Gadd45α leading to p38 activation and ultimately an increase in sFlt-1 and sEng secretion in HUVECs has concurrently been established. Our study opens up a promising new avenue of investigation for increasing the understanding of the origin of sFlt-1 and sEng in PE and provides novel therapeutic targets for pregnancy complications arising from placental endothelial dysfunction.

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

Access this article

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
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Reference

  • ACOG Committee on Obstetric Practice (2002) ACOG practice bulletin. Diagnosis and management of pre-eclampsia and eclampsia. Number 33, January 2002. American College of Obstetricians and Gynecologists. Obstet Gynecol 99:67–75

    Article  Google Scholar 

  • Ahmad S, Ahmed A (2004) Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res 95:884–891

    Article  PubMed  CAS  Google Scholar 

  • Amanullah A, Azam N, Balliet A, Hollander C, Hoffman B, Fornace A, Liebermann D (2003) Cell signalling: cell survival and a Gadd45-factor deficiency. Nature 424:741–742

    Article  PubMed  CAS  Google Scholar 

  • Bergmann A, Ahmad S, Cudmore M, Gruber AD, Wittschen P, Lindenmaier W, Christofori G, Gross V, Gonzalves ACh, Grone H-J, Ahmed A, Weich HA (2010) Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. J Cell Mol Med 14:1857–1867

    Article  PubMed  CAS  Google Scholar 

  • Bulavin DV, Kovalsky O, Hollander MC, Fornace AJ (2003) Loss of oncogenic H-ras-induced cell cycle arrest and p38 mitogen-activated protein kinase activation by disruption of gadd45a. Mol Cell Biol 23:3859–3871

    Article  PubMed  CAS  Google Scholar 

  • Burton GJ, Yung HW, Cindrova-Davies T, Charnock-Jones DS (2009) Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia. Placenta 30:S43–S48

    Article  PubMed  Google Scholar 

  • Chaiworapongsa T, Romero R, Kim YM, Kim GJ, Kim MR, Espinoza J, Bujold E, Goncalves L, Gomez R, Edwin S, Mazor M (2005) Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia. J Matern Fetal Neonatal Med 17:3–18

    Article  PubMed  CAS  Google Scholar 

  • Chambers JC, Fusi L, Malik IS, Haskard DO, De Swiet M, Kooner JS (2001) Association of maternal endothelial dysfunction with preeclampsia. JAMA 285:1607–1612

    Article  PubMed  CAS  Google Scholar 

  • Cindrova-Davies T (2009) Gabor Than Award Lecture 2008: pre-eclampsia—from placental oxidative stress to maternal endothelial dysfunction. Placenta 30:S55–S65

    Article  PubMed  Google Scholar 

  • Cindrova-Davies T, Spasic-Boskovic O, Jauniaux E, Charnock-Jones DS, Burton GJ (2007) Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress—effects of antioxidant vitamins. Am J Pathol 170:1511–1520

    Article  PubMed  CAS  Google Scholar 

  • Cobellis L, Mastrogiacomo A, Federico E, Schettino MT, De Falco M, Manente L, Coppola G, Torella M, Colacurci N, De Luca A (2007) Distribution of Notch protein members in normal and preeclampsia-complicated placentas. Cell Tissue Res 330:527–534

    Article  PubMed  CAS  Google Scholar 

  • Cudmore M, Ahmad S, Al-Ani B, Fujisawa T, Coxall H, Chudasama K, Devey LR, Wigmore SJ, Abbas A, Hewett PW, Ahmed A (2007) Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1. Circulation 115:1789–1797

    Article  PubMed  CAS  Google Scholar 

  • Dhar-Mascareno M, Carcamo JM, Golde DW (2005) Hypoxia-reoxygenation-induced mitochondrial damage and apoptosis in human endothelial cells are inhibited by vitamin C. Free Radic Biol Med 38:1311–1322

    Article  PubMed  CAS  Google Scholar 

  • Gilbert JS, Gilbert SAB, Arany M, Granger JP (2009) Hypertension produced by placental ischemia in pregnant rats is associated with increased soluble endoglin expression. Hypertension 53:399–403

    Article  PubMed  CAS  Google Scholar 

  • Gupta M, Gupta SK, Hoffman B, Liebermann DA (2006) Gadd45a and Gadd45b protect hematopoietic cells from UV-induced apoptosis via distinct signaling pathways, including p38 activation and JNK inhibition. J Biol Chem 281:17552–17558

    Article  PubMed  CAS  Google Scholar 

  • Harkin DP, Bean JM, Miklos D, Song YH, Truong VB, Englert C, Christians FC, Ellisen LW, Maheswaran S, Oliner JD, Haber DA (1999) Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 97:575–586

    Article  PubMed  CAS  Google Scholar 

  • Hertig A, Berkane N, Lefevre G, Toumi K, Marti H-P, Capeau J, Uzan S, Rondeau E (2004) Maternal serum sFlt1 concentration is an early and reliable predictive marker of preeclampsia. Clin Chem 50:1702–1703

    Article  PubMed  CAS  Google Scholar 

  • Hildesheim J, Bulavin DV, Anver MR, Alvord WG, Hollander MC, Vardanian L, Fornace AJ (2002) Gadd45a protects against UV irradiation-induced skin tumors, and promotes apoptosis and stress signaling via MAPK and p53. Cancer Res 62:7305–7315

    PubMed  CAS  Google Scholar 

  • Hollander MC, Sheikh MS, Bulavin DV, Lundgren K, Augeri-Henmueller L, Shehee R, Molinaro TA, Kim KE, Tolosa E, Ashwell JD, Rosenberg MP, Zhan QM, Fernandez-Salguero PM, Morgan WF, Deng CX, Fornace AJ (1999) Genomic instability in Gadd45a-deficient mice. Nat Genet 23:176–184

    Article  PubMed  CAS  Google Scholar 

  • Hung T-H, Skepper JN, Burton GJ (2001) In vitro ischemia-reperfusion injury in term human placenta as a model for oxidative stress in pathological pregnancies. Am J Pathol 159:1031–1043

    Article  PubMed  CAS  Google Scholar 

  • Hung T-H, Skepper JN, Charnock-Jones DS, Burton GJ (2002) Hypoxia-reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. Circ Res 90:1274–1281

    Article  PubMed  CAS  Google Scholar 

  • Irminger-Finger I, Jastrow N, Irion O (2008) Preeclampsia: a danger growing in disguise. Int J Biochem Cell Biol 40:1979–1983

    Article  PubMed  CAS  Google Scholar 

  • Jaffe E, Nachman R, Becker C, Minick C (1973) Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest 52:2745

    Article  PubMed  CAS  Google Scholar 

  • Lash GE, Naruse K, Innes BA, Robson SC, Searle RF, Bulmer JN (2010) Secretion of angiogenic growth factors by villous cytotrophoblast and extravillous trophoblast in early human pregnancy. Placenta 31:545–548

    Article  PubMed  CAS  Google Scholar 

  • Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA (2004) Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683

    Article  PubMed  CAS  Google Scholar 

  • Levine R, Lam C, Qian C, Yu K, Maynard S, Sibai B, Romero R, Epstein F, Karumanchi A (2005) Soluble endoglin, a novel circulating anti-angiogenic factor in preeclampsia (PE). Am J Obstet Gynecol 193:31

    Google Scholar 

  • Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai BM, Epstein FH, Romero R, Thadhani R, Karumanchi SA, Grp CS (2006) Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 355:992–1005

    Article  PubMed  CAS  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(T)(−Delta Delta C) method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  • Marconcini L, Marchio S, Morbidelli L, Cartocci E, Albini A, Ziche M, Bussolino F, Oliviero S (1999) c-fos-induced growth factor/vascular endothelial growth factor D induces angiogenesis in vivo and in vitro. Proc Natl Acad Sci USA 96:9671–9676

    Article  PubMed  CAS  Google Scholar 

  • Maynard SE, Min JY, Merchan J, Lim KH, Li JY, Mondal S, Libermann TA, Morgan LP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfimction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111:649–658

    PubMed  CAS  Google Scholar 

  • Mutter WP, Karumanchi SA (2008) Molecular mechanisms of preeclampsia. Microvasc Res 75:1–8

    Article  PubMed  CAS  Google Scholar 

  • Redman CWG, Sargent IL (2000) Placental debris, oxidative stress and pre-eclampsia. Placenta 21:597–602

    Article  PubMed  CAS  Google Scholar 

  • Redman CW, Sargent IL (2005) Latest advances in understanding preeclampsia. Science 308:1592–1594

    Article  PubMed  CAS  Google Scholar 

  • Roberts JM, Hubel CA (1999) Is oxidative stress the link in the two-stage model of pre-eclampsia? Lancet 354:788–789

    PubMed  CAS  Google Scholar 

  • Salahuddin S, Lee Y, Vadnais M, Sachs BP, Karumanchi SA, Lim KH (2007) Diagnostic utility of soluble fms-like tyrosine kinase 1 and soluble endoglin in hypertensive diseases of pregnancy. Am J Obstet Gynecol 197:28.e1-28.e6

    Article  Google Scholar 

  • Shin JK, Jeong YT, Jo HC, Kang MY, Chang IS, Baek JC, Park JK, Lee SA, Lee JH, Choi WS, Paik WY (2009) Increased interaction between heat shock protein 27 and mitogen-activated protein kinase (p38 and extracellular signal-regulated kinase) in pre-eclamptic placentas. J Obstet Gynaecol Res 35:888–894

    Article  PubMed  CAS  Google Scholar 

  • Takekawa M, Saito H (1998) A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell 95:521–530

    Article  PubMed  CAS  Google Scholar 

  • Therade-Matharan S, Laemmel E, Duranteau J, Vicaut E (2004) Reoxygenation after hypoxia and glucose depletion causes reactive oxygen species production by mitochondria in HUVEC. Am J Physiol Regul Integr Comp Physiol 287:R1037–R1043

    Article  PubMed  CAS  Google Scholar 

  • Tretyakov AV, Farber HW (1995) Endothelial-cell tolerance to hypoxia—potential role of purine nucleotide phosphates. J Clin Invest 95:738–744

    Article  PubMed  CAS  Google Scholar 

  • Tront JS, Hoffman B, Liebermann DA (2006) Gadd45a suppresses ras-driven mammary tumorigenesis by activation of c-Jun NH2-terminal kinase and p38 stress signaling resulting in apoptosis and senescence. Cancer Res 66:8448–8454

    Article  PubMed  CAS  Google Scholar 

  • Tskitishvili E, Sharentuya N, Temma-Asano K, Mimura K, Kinugasa-Taniguchi Y, Kanagawa T, Fukuda H, Kimura T, Tomimatsu T, Shimoya K (2010) Oxidative stress-induced S100B protein from placenta and amnion affects soluble endoglin release from endothelial cells. Mol Hum Reprod 16:188–199

    Article  PubMed  CAS  Google Scholar 

  • Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D'Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M, Karumanchi SA (2006) Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 12:642–649

    Article  PubMed  CAS  Google Scholar 

  • Wang Y-H, Xiong J, Wang S-F, Yu Y, Wang B, Chen Y-X, Shi H-F, Qiu Y (2010) Lentivirus-mediated shRNA targeting insulin-like growth factor-1 receptor (IGF-1R) enhances chemosensitivity of osteosarcoma cells in vitro and in vivo. Mol Cell Biochem 341:225–233

    Article  PubMed  CAS  Google Scholar 

  • Xiong YL, Liebermann DA, Tront JS, Holtzman EJ, Huang YJ, Hoffman B, Geifman-Holtzman O (2009) Gadd45a stress signaling regulates sFlt-1 expression in preeclampsia. J Cell Physiol 220:632–639

    Article  PubMed  CAS  Google Scholar 

  • Zerbini LF, Wang YH, Czibere A, Correa RG, Cho JY, Ijiri K, Wei WJ, Joseph M, Gu XS, Grall F, Goldring MB, Zhou JR, Libermann TA (2004) NF-kappa B-mediated repression of growth arrest- and DNA-damage-inducible proteins 45 alpha and gamma is essential for cancer cell survival. Proc Natl Acad Sci USA 101:13618–13623

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

We are grateful to Gang Liao and Bo Liu for excellent technical assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hong-bo Qi.

Additional information

Xin Luo and Zhen-wei Yao contributed equally to this project and should be considered as co-first authors.

This work was supported by grant no. 81070502 from the National Natural Science Foundation of China.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luo, X., Yao, Zw., Qi, Hb. et al. Gadd45α as an upstream signaling molecule of p38 MAPK triggers oxidative stress-induced sFlt-1 and sEng upregulation in preeclampsia. Cell Tissue Res 344, 551–565 (2011). https://doi.org/10.1007/s00441-011-1164-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-011-1164-z

Keywords

Navigation