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DOI: 10.1055/s-0033-1360133
New Insights into the Pathogenesis of Preeclampsia – The Role of Nrf2 Activators and their Potential Therapeutic Impact
Neue Einblicke in der Pathogenese der Präeklampsie – die Rolle von Nrf2-Aktivatoren und ihre potenzielle therapeutische WirkungPublication History
received 05 August 2013
revised 25 October 2013
accepted 06 November 2013
Publication Date:
20 December 2013 (online)
![](https://www.thieme-connect.de/media/gebfra/201312/lookinside/thumbnails/10.1055-s-0033-1360133-1.jpg)
Abstract
Preeclampsia (PE), characterized by proteinuric hypertension and occurring in 2–3 % of all pregnancies, is one of the leading causes of maternal, fetal and neonatal morbidity and mortality. The etiology of PE still remains unclear and current treatments for this devastating disorder are still limited to symptomatic therapies. Placental oxidative stress may be a key intermediate step in the pathogenesis of PE; it has been related to excessive secretion of multiple antiangiogenic factors, mainly soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). The nuclear factor-erythroid 2-like 2 (Nrf2) pathway is one of the most important systems that enhance cellular protection against oxidative stress. Nrf2 serves as a master transcriptional regulator of the basal and inducible expression of a multitude of genes encoding detoxification enzymes and antioxidative proteins. Evidence for a link between Nrf2 and restoring the balance between pro- and antiangiogenic factors mainly through its downstream target protein heme oxygenase-1 (HO-1) has lately been discussed. HO-1 metabolizes heme to biliverdin, iron and carbon monoxide (CO). CO enhances vascular endothelial growth factor (VEGF) synthesis in vascular smooth muscle and promotes its relaxation and hence vasodilatation. In addition, HO-1 has been shown in vitro to inhibit the production of sFlt-1. A recent animal study demonstrated that the induction of HO-1 in a mouse model of PE attenuates the induced hypertension in pregnant mice. This provides compelling evidence for the protective role of Nrf2/HO-1 in pregnancy and identifies this pathway as a target to treat women with PE. We summarize the recent findings on the involvement of Nrf2 in the pathogenesis of PE, and provide an overview of the possible beneficial effects of Nrf2 inducers in PE.
Zusammenfassung
Präeklampsie (PE) ist charakterisiert durch Gestationshypertonie und Proteinurie; mit einer Prävalenz von 2 bis 3 % zählt sie zu den häufigsten Schwangerschaftserkrankungen. Präeklampsie gehört zu den führenden Ursachen für fetale, neonatale und mütterliche Morbidität und Mortalität. Die Ätiologie dieses Syndroms ist noch unbekannt, und die Behandlung richtet sich daher nach den Symptomen. Studien haben gezeigt, dass oxidativer Stress in der Plazenta eine wichtige Rolle bei der Pathogenese der Präeklampsie spielen könnte. Plazentaler oxidativer Stress könnte zu einer erhöhten Freisetzung von antiangiogenetischen Faktoren wie fms-like Tyrosine Kinase-1 (sFlt-1) und Soluble Endoglin (sEng) führen. Der Nuclear-Factor-Erythroid-like-2-(Nrf2-)Signalweg ist ein wichtiges System, das die Zellen vor oxidativen Stress schützt. Die Expression vieler antioxidativer Enzyme wird von Nrf2 verstärkt. Es wurde ferner berichtet, dass das Nrf2-System eine Rolle bei der Regulierung der Balance von pro- und antiangiogenen Faktoren spielt, indem es das Zielprotein Hämoxygenase-1 (HO-1) hochreguliert. HO-1 katalysiert die Oxidation von Häm zu Biliverdin, Eisen und Kohlenmonoxide (CO). CO stimuliert die Proteinsynthese des vaskulären endothelialen Wachstumsfaktors VEGF in vaskulären glatten Muskelzellen, und kann auch die Relaxation der glatten Muskulatur (Gefäßerweiterung) induzieren. Zudem kann HO-1 in vitro die Freisetzung von sFlt-1 hemmen. Darüber hinaus wurde kürzlich in Studien gezeigt, dass die Aktivierung von HO-1 in verschiedenen Tiermodellen für Präeklampsie zu einer Blutdrucksenkung führt. Diese Studien zeigen, dass der Nrf2/HO-1 Signalweg eine präventive Rolle bei Präeklampsie spielen könnte. Ziel dieser Übersichtsarbeit ist es, die neuesten wissenschaftlichen Studien zur Beteiligung von Nrf2 an der Pathogenese von Präeklampsie zusammenzufassen. Zudem möchten wir einen Überblick über das therapeutische Potenzial von Nrf2-Aktivatoren bei der Präeklampsie geben.
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References
- 1 Steegers EA, von Dadelszen P, Duvekot JJ et al. Pre-eclampsia. Lancet 2010; 376: 631-644
- 2 Cantwell R, Clutton-Brock T, Cooper G et al. Saving Mothersʼ Lives: Reviewing maternal deaths to make motherhood safer: 2006–2008. The Eighth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. BJOG 2011; 118 (Suppl. 01) 1-203
- 3 ACOG. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol 2002; 99: 159-167
- 4 Brown MC, Best KE, Pearce MS et al. Cardiovascular disease risk in women with pre-eclampsia: systematic review and meta-analysis. Eur J Epidemiol 2013; 28: 1-19
- 5 Schausberger CE, Jacobs VR, Bogner G et al. Hypertensive disorders of pregnancy – a life-long risk?. Geburtsh Frauenheilk 2013; 73: 47-52
- 6 van Rijn BB, Nijdam ME, Bruinse HW et al. Cardiovascular disease risk factors in women with a history of early-onset preeclampsia. Obstet Gynecol 2013; 121: 1040-1048
- 7 Schlembach D. Pre-eclampsia–still a disease of theories. Fukushima J Med Sci 2003; 49: 69-115
- 8 Tallarek A-C, Huppertz B, Stepan H. Preeclampsia – aetiology, current diagnostics and clinical management, new therapy options and future perspectives. Geburtsh Frauenheilk 2012; 72: 1107-1116
- 9 Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science 2005; 308: 1592-1594
- 10 Kaufmann P, Black S, Huppertz B. Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod 2003; 69: 1-7
- 11 Murray AJ. Oxygen delivery and fetal-placental growth: beyond a question of supply and demand?. Placenta 2012; 33 (Suppl. 02) e16-e22
- 12 Vanderlelie J, Venardos K, Clifton VL et al. Increased biological oxidation and reduced anti-oxidant enzyme activity in pre-eclamptic placentae. Placenta 2005; 26: 53-58
- 13 Kaspar JW, Niture SK, Jaiswal AK. Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med 2009; 47: 1304-1309
- 14 Wruck CJ, Streetz K, Pavic G et al. Nrf2 induces interleukin-6 (IL-6) expression via an antioxidant response element within the IL-6 promoter. J Biol Chem 2011; 286: 4493-4499
- 15 Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 2007; 47: 89-116
- 16 Wruck CJ, Huppertz B, Bose P et al. Role of a fetal defence mechanism against oxidative stress in the aetiology of preeclampsia. Histopathology 2009; 55: 102-106
- 17 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: 42863-42872
- 18 Kweider N, Huppertz B, Wruck CJ et al. 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
- 19 Belo L, Caslake M, Santos-Silva A et al. LDL size, total antioxidant status and oxidised LDL in normal human pregnancy: a longitudinal study. Atherosclerosis 2004; 177: 391-399
- 20 Redman CW. Preeclampsia: a multi-stress disorder. Rev Med Interne 2011; 32 (Suppl. 01) S41-S44
- 21 Burton GJ, Jauniaux E. Oxidative stress. Best Pract Res Clin Obstet Gynaecol 2011; 25: 287-299
- 22 Roberts JM, Taylor RN, Musci TJ et al. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol 1989; 161: 1200-1204
- 23 Huppertz B, Abe E, Murthi P et al. Placental angiogenesis, maternal and fetal vessels – a workshop report. Placenta 2007; 28 (Suppl. A) S94-S96
- 24 Kadyrov M, Kingdom JC, Huppertz B. Divergent trophoblast invasion and apoptosis in placental bed spiral arteries from pregnancies complicated by maternal anemia and early-onset preeclampsia/intrauterine growth restriction. Am J Obstet Gynecol 2006; 194: 557-563
- 25 Miranda Guisado ML, Vallejo-Vaz AJ, Garcia Junco PS et al. Abnormal levels of antioxidant defenses in a large sample of patients with hypertensive disorders of pregnancy. Hypertens Res 2012; 35: 274-278
- 26 Stepan H, Heihoff-Klose A, Faber R. Reduced antioxidant capacity in second-trimester pregnancies with pathological uterine perfusion. Ultrasound Obstet Gynecol 2004; 23: 579-583
- 27 Roberts JM, Hubel CA. Is oxidative stress the link in the two-stage model of pre-eclampsia?. Lancet 1999; 354: 788-789
- 28 Hung TH, Skepper JN, Burton GJ. In vitro ischemia-reperfusion injury in term human placenta as a model for oxidative stress in pathological pregnancies. Am J Pathol 2001; 159: 1031-1043
- 29 Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells 2011; 16: 123-140
- 30 Lee JM, Li J, Johnson DA et al. Nrf2, a multi-organ protector?. FASEB J 2005; 19: 1061-1066
- 31 Brandenburg LO, Kipp M, Lucius R et al. Sulforaphane suppresses LPS-induced inflammation in primary rat microglia. Inflamm Res 2010; 59: 443-450
- 32 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-E1870
- 33 Mann GE, Niehueser-Saran J, Watson A et al. Nrf2/ARE regulated antioxidant gene expression in endothelial and smooth muscle cells in oxidative stress: implications for atherosclerosis and preeclampsia. Sheng Li Xue Bao 2007; 59: 117-127
- 34 Valcarcel-Ares MN, Gautam T, Warrington JP et al. Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging. J Gerontol A Biol Sci Med Sci 2012; 67: 821-829
- 35 Loset M, Mundal SB, Johnson MP et al. A transcriptional profile of the decidua in preeclampsia. Am J Obstet Gynecol 2011; 204: 84e81-84e27
- 36 Bilban M, Haslinger P, Prast J et al. Identification of novel trophoblast invasion-related genes: heme oxygenase-1 controls motility via peroxisome proliferator-activated receptor gamma. Endocrinology 2009; 150: 1000-1013
- 37 Barbagallo I, Galvano F, Frigiola A et al. Potential therapeutic effects of natural heme oxygenase-1 inducers in cardiovascular diseases. Antioxid Redox Signal 2013; 18: 507-521
- 38 Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A 1968; 61: 748-755
- 39 Levytska K, Kingdom J, Baczyk D et al. Heme oxygenase-1 in placental development and pathology. Placenta 2013; 34: 291-298
- 40 Cudmore M, Ahmad S, Al-Ani B et al. Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1. Circulation 2007; 115: 1789-1797
- 41 Verlohren S, Herraiz I, Lapaire O et al. The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. Am J Obstet Gynecol 2012; 206: 58e51-58e58
- 42 Stepan H, Ebert T, Schrey S et al. Serum levels of angiopoietin-related growth factor are increased in preeclampsia. Am J Hypertens 2009; 22: 314-318
- 43 Stepan H. Angiogenic factors and pre-eclampsia: an early marker is needed. Clin Sci 2009; 116: 231-232
- 44 Fasshauer M, Waldeyer T, Seeger J et al. Circulating high-molecular-weight adiponectin is upregulated in preeclampsia and is related to insulin sensitivity and renal function. Eur J Endocrinol 2008; 158: 197-201
- 45 George EM, Hosick PA, Stec DE et al. Heme oxygenase inhibition increases blood pressure in pregnant rats. Am J Hypertens 2013; 26: 924-930
- 46 Grochot-Przeczek A, Dulak J, Jozkowicz A. Heme oxygenase-1 in neovascularisation: a diabetic perspective. Thromb Haemost 2010; 104: 424-431
- 47 Zhao H, Wong RJ, Kalish FS et al. Effect of heme oxygenase-1 deficiency on placental development. Placenta 2009; 30: 861-868
- 48 Grosser N, Hemmerle A, Berndt G et al. The antioxidant defense protein heme oxygenase 1 is a novel target for statins in endothelial cells. Free Radic Biol Med 2004; 37: 2064-2071
- 49 Deng YM, Wu BJ, Witting PK et al. Probucol protects against smooth muscle cell proliferation by upregulating heme oxygenase-1. Circulation 2004; 110: 1855-1860
- 50 Wruck CJ, Gotz ME, Herdegen T et al. Kavalactones protect neural cells against amyloid beta peptide-induced neurotoxicity via extracellular signal-regulated kinase 1/2-dependent nuclear factor erythroid 2-related factor 2 activation. Mol Pharmacol 2008; 73: 1785-1795
- 51 Wu L, Juurlink BH. The impaired glutathione system and its up-regulation by sulforaphane in vascular smooth muscle cells from spontaneously hypertensive rats. J Hypertens 2001; 19: 1819-1825
- 52 Guan SP, Tee W, Ng DS et al. Andrographolide protects against cigarette smoke-induced oxidative lung injury via augmentation of Nrf2 activity. Br J Pharmacol 2013; 168: 1707-1718
- 53 Poston L, Briley AL, Seed PT et al. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006; 367: 1145-1154
- 54 Rumbold AR, Crowther CA, Haslam RR et al. Vitamins C and E and the risks of preeclampsia and perinatal complications. N Engl J Med 2006; 354: 1796-1806
- 55 Elsen C, Rivas-Echeverría C, Sahland K et al. Vitamins E, A and B2 as possible risk factors for preeclampsia – under consideration of the PROPER study (“Prevention of preeclampsia by high-dose riboflavin supplementation”). Geburtsh Frauenheilk 2012; 72: 846-852
- 56 Voelkel NF, Bogaard HJ, Al Husseini A et al. Antioxidants for the treatment of patients with severe angioproliferative pulmonary hypertension?. Antioxid Redox Signal 2013; 18: 1810-1817
- 57 Gomez-Guzman M, Jimenez R, Sanchez M et al. Epicatechin lowers blood pressure, restores endothelial function, and decreases oxidative stress and endothelin-1 and NADPH oxidase activity in DOCA-salt hypertension. Free Radic Biol Med 2012; 52: 70-79
- 58 Kim SB, Eskiocak U, Ly P. Bardoxolone-methyl (CDDO-Me): an antioxidant, antiinflammatory modulator is a novel radiation countermeasure and mitigator. In: Proceedings of the 22nd Annual NASA Space Radiation Investigatorsʼ Workshop 2011; Sep 2011.
- 59 Rojas-Rivera J, Ortiz A, Egido J. Antioxidants in kidney diseases: the impact of bardoxolone methyl. Int J Nephrol 2012; 2012: 321714
- 60 Vanhees K, van Schooten FJ, van Waalwijk van Doorn-Khosrovani SB et al. Intrauterine exposure to flavonoids modifies antioxidant status at adulthood and decreases oxidative stress-induced DNA damage. Free Radic Biol Med 2013; 57: 154-161