Preeclampsia and Gestational Hypertension: Biochemical and Antioxidant Features in Vitro Might Help Understand Different Outcomes

 

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Abstract

Objective Gestational hypertension (GH) is characterized by increased blood pressure after the 20^th gestational week; the presence of proteinuria and/or signs of end-organ damage indicate preeclampsia (PE). Heme oxygenase-1 (HO-1) is an antioxidant enzyme with an important role in maintaining endothelial function, and induction of HO-1 by certain molecules shows potential in attenuating the condition's effects over endothelial tissue. HO-1 production can also be stimulated by potassium iodide (KI). Therefore, we evaluated the effects of KI over HO-1 expression in human umbilical vein endothelial cells (HUVECs) incubated with plasma from women diagnosed with GH or PE.

Methods Human umbilical vein endothelial cells were incubated with a pool of plasma of healthy pregnant women (n = 12), pregnant women diagnosed with GH (n = 10) or preeclamptic women (n = 11) with or without the addition of KI for 24 hours to evaluate its effect on this enzyme expression. Analysis of variance was performed followed by Dunnet's test for multiple comparisons between groups only or between groups with addition of KI (p ≤ 0.05).

Results KI solution (1,000 µM) reduced HO-1 in the gestational hypertension group (p = 0.0018) and cytotoxicity in the preeclamptic group (p = 0.0143); treatment with KI reduced plasma cytotoxicity but did not affect the preeclamptic group's HO-1 expression.

Conclusion Our findings suggest that KI alleviates oxidative stress leading to decreased HO-1 expression; plasma from preeclamptic women did not induce the enzyme's expression in HUVECs, and we hypothesize that this is possibly due to inhibitory post-transcriptional mechanisms in response to overexpression of this enzyme during early pregnancy.

Resumo

Objetivo A hipertensão gestacional (GH) é caracterizada pelo aumento da pressão sanguínea após a 20ª semana de gestação; a presença de proteinuria e/ou sinais de danos a órgãos como rins, fígado e cérebro indicam pré-eclâmpsia (PE). A heme oxigenase-1 (HO-1) é uma enzima antioxidante com um papel importante na manutenção da função endotelial, e a sua indução por certas moléculas se mostra potencialmente benéfica frente à característica deletéria destas condições sobre o endotélio. Já foi demonstrado anteriormente que a produção de HO-1 pode ser induzida por iodeto de potássio (KI). Portanto, nós avaliamos os efeitos do KI sobre a citotoxicidade e expressão de HO-1 por células de veia de cordão umbilical humano (HUVECs) após incubação com o plasma de mulheres diagnosticadas com GH ou PE.

Métodos Células de veia de cordão umbilical humano foram incubadas com pool de plasma de gestantes saudáveis (n = 12), gestantes com GH (n = 10) ou gestantes com PE (n = 11) com ou sem a adição de KI por 24 horas para avaliar a citotoxicidade através da dosagem de lactato desidrogenase e produção de HO-1 por ELISA. Foi realizada ANOVA seguida de teste de Dunnet para múltiplas comparações entre os grupos estudados, considerando significativos valores de p ≤ 0,05.

Resultados A solução de KI (1.000 µM) reduziu a produção de HO-1 no grupo GH (p = 0.0018) e a citotoxicidade no grupo PE (p = 0.0143); o tratamento com KI não afetou a produção de HO-1 por HUVECs incubadas com o plasma do grupo PE.

Conclusão Nossos achados sugerem que o KI atenua os efeitos do plasma de gestantes com GH ocasionando a diminuição da produção de HO-1; plasma do grupo PE não induziu a produção de HO-1 em HUVECs em comparação ao grupo saudável, e nossa hipótese é a de que tal achado pode ser devido a mecanismos pós-transcricionais em resposta a uma superestimulação da produção de HO-1 nos estágios iniciais da gravidez.

Contributors

All of the authors contributed with the project and data interpretation, the writing of the article, the critical review of the intellectual content, and with the final approval of the version to be published.

Publication History

Received: 31 August 2020

Accepted: 05 October 2021

Article published online:
21 December 2021

© 2021. Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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• References

• 1 American College of Obstetricians. Gynecologists' Task Force on Hypertension in Pregnancy Hypertension in pregnancy. Obstet Gynecol 2013; 122 (05) 1122-1131 DOI: 10.1097/01.AOG.0000437382.03963.88.
  CrossrefPubMedGoogle Scholar
• 2 Brown MA, Magee LA, Kenny LC, Karumanchi SA, McCarthy FP, Saito S. et al; International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice. Hypertension 2018; 72 (01) 24-43 DOI: 10.1161/HYPERTENSIONAHA.117.10803.
  CrossrefPubMedGoogle Scholar
• 3 Sullivan SD, Umans JG, Ratner R. Hypertension complicating diabetic pregnancies: pathophysiology, management, and controversies. J Clin Hypertens (Greenwich) 2011; 13 (04) 275-284 DOI: 10.1111/j.1751-7176.2011.00440.x.
  CrossrefPubMedGoogle Scholar
• 4 Roberts JM, Pearson G, Cutler J, Lindheimer M. NHLBI Working Group on Research on Hypertension During Pregnancy. Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy. Hypertension 2003; 41 (03) 437-445 DOI: 10.1161/01.HYP.0000054981.03589.E9.
  CrossrefPubMedGoogle Scholar
• 5 Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet 2006; 367 (9516): 1066-1074 DOI: 10.1016/S0140-6736(06)68397-9.
  CrossrefPubMedGoogle Scholar
• 6 Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol 2011; 25 (04) 391-403 DOI: 10.1016/j.bpobgyn.2011.01.006.
  CrossrefPubMedGoogle Scholar
• 7 Roberts JM, Hubel CA. The two stage model of preeclampsia: variations on the theme. Placenta 2009; 30 (Suppl A): S32-S37 DOI: 10.1016/j.placenta.2008.11.009.
  CrossrefPubMedGoogle Scholar
• 8 Myatt L, Redman CW, Staff AC, Hansson S, Wilson ML, Laivuori H. et al; Global Pregnancy CoLaboratory. Strategy for standardization of preeclampsia research study design. Hypertension 2014; 63 (06) 1293-1301 DOI: 10.1161/HYPERTENSIONAHA.113.02664.
  CrossrefPubMedGoogle Scholar
• 9 Granger JP, Alexander BT, Llinas MT, Bennett WA, Khalil RA. Pathophysiology of hypertension during preeclampsia linking placental ischemia with endothelial dysfunction. Hypertension 2001; 38 (3 Pt 2): 718-722 DOI: 10.1161/01.hyp.38.3.718.
  CrossrefPubMedGoogle Scholar
• 10 Erdemli HK, Yıldırımlar 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 (04) 488-497 DOI: 10.3109/10641955.2014.946613.
  CrossrefPubMedGoogle Scholar
• 11 Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 2016; 73 (17) 3221-3247 DOI: 10.1007/s00018-016-2223-0.
  CrossrefPubMedGoogle Scholar
• 12 George EM, Cockrell K, Aranay M, Csongradi E, Stec DE, Granger JP. Induction of heme oxygenase 1 attenuates placental ischemia-induced hypertension. Hypertension 2011; 57 (05) 941-948 DOI: 10.1161/HYPERTENSIONAHA.111.169755.
  CrossrefPubMedGoogle Scholar
• 13 Caldeira-Dias M, Montenegro MF, Bettiol H, Barbieri MA, Cardoso VC, Cavalli RC. et al. Resveratrol improves endothelial cell markers impaired by plasma incubation from women who subsequently develop preeclampsia. Hypertens Res 2019; 42 (08) 1166-1174 DOI: 10.1038/s41440-019-0243-5.
  CrossrefPubMedGoogle Scholar
• 14 Aceves C, Anguiano B, Delgado G. The extrathyronine actions of iodine as antioxidant, apoptotic, and differentiation factor in various tissues. Thyroid 2013; 23 (08) 938-946 DOI: 10.1089/thy.2012.0579.
  CrossrefPubMedGoogle Scholar
• 15 Ben-Yehuda Greenwald M, Frušić-Zlotkin M, Soroka Y, Ben-Sasson S, Bianco-Peled H, Kohen R. A novel role of topical iodine in skin: Activation of the Nrf2 pathway. Free Radic Biol Med 2017; 104: 238-248 DOI: 10.1016/j.freeradbiomed.2017.01.011.
  CrossrefPubMedGoogle Scholar
• 16 Martinez NF, Filgueira GC, Machado JdeS, Dos Santos JE, Sandrim VC, Duarte G. et al. [Clinical and laboratory characteristics of pregnant women with preeclampsia versus gestational hypertension]. Rev Bras Ginecol Obstet 2014; 36 (10) 461-466 DOI: 10.1590/so100-720320140005029. Portuguese.
  CrossrefPubMedGoogle Scholar
• 17 Benzie IF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem 1996; 239 (01) 70-76 DOI: 10.1006/abio.1996.0292.
  CrossrefPubMedGoogle Scholar
• 18 Luizon MR, Palei AC, Cavalli RC, Sandrim VC. Pharmacogenetics in the treatment of pre-eclampsia: current findings, challenges and perspectives. Pharmacogenomics 2017; 18 (06) 571-583 DOI: 10.2217/pgs-2016-0198.
  CrossrefPubMedGoogle Scholar
• 19 Gomes HF, Palei AC, Machado JS, da Silva LM, Montenegro MF, Jordão AA. et al. Assessment of oxidative status markers and NO bioavailability in hypertensive disorders of pregnancy. J Hum Hypertens 2013; 27 (06) 345-348 DOI: 10.1038/jhh.2012.58.
  CrossrefPubMedGoogle Scholar
• 20 Harsem NK, Braekke K, Staff AC. Augmented oxidative stress as well as antioxidant capacity in maternal circulation in preeclampsia. Eur J Obstet Gynecol Reprod Biol 2006; 128 (1-2): 209-215 DOI: 10.1016/j.ejogrb.2005.11.014.
  CrossrefPubMedGoogle Scholar
• 21 Taravati A, Tohidi F. Comprehensive analysis of oxidative stress markers and antioxidants status in preeclampsia. Taiwan J Obstet Gynecol 2018; 57 (06) 779-790 DOI: 10.1016/j.tjog.2018.10.002.
  CrossrefPubMedGoogle Scholar
• 22 Gamon LF, Dieterich S, Ignasiak MT, Schrameyer V, Davies MJ. Iodide modulates protein damage induced by the inflammation-associated heme enzyme myeloperoxidase. Redox Biol 2020; 28: 101331 DOI: 10.1016/j.redox.2019.101331.
  CrossrefPubMedGoogle Scholar
• 23 Gandley RE, Rohland J, Zhou Y, Shibata E, Harger GF, Rajakumar A. et al. Increased myeloperoxidase in the placenta and circulation of women with preeclampsia. Hypertension 2008; 52 (02) 387-393 DOI: 10.1161/HYPERTENSIONAHA.107.107532.
  CrossrefPubMedGoogle Scholar
• 24 Tatzber F, Griebenow S, Wonisch W, Winkler R. Dual method for the determination of peroxidase activity and total peroxides-iodide leads to a significant increase of peroxidase activity in human sera. Anal Biochem 2003; 316 (02) 147-153 DOI: 10.1016/s0003-2697(02)00652-8.
  CrossrefPubMedGoogle Scholar
• 25 Focaccetti C, Bruno A, Magnani E, Bartolini D, Principi E, Dallaglio K. et al. Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes. PLoS One 2015; 10 (02) e0115686 DOI: 10.1371/journal.pone.0115686.
  CrossrefPubMedGoogle Scholar
• 26 Funchal C, Latini A, Jacques-Silva MC. et al. Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Neurochem Int 2006; 49 (07) 640-650 DOI: 10.1016/j.neuint.2006.05.007.
  CrossrefPubMedGoogle Scholar
• 27 Vitoratos N, Papakonstantinou K, Deliveliotou A, Economou E, Panoulis C, Hassiakos D. et al. Antepartum and postpartum serum heme oxygenase-1 levels in preeclamptic and normotensive pregnant women. In Vivo 2011; 25 (03) 445-450
  PubMedGoogle Scholar
• 28 Sandrim VC, Caldeira-Dias M, Bettiol H, Barbieri MA, Cardoso VC, Cavalli RC. Circulating heme oxygenase-1: not a predictor of preeclampsia but highly expressed in pregnant women who subsequently develop severe preeclampsia. Oxid Med Cell Longev 2018; 2018: 6035868 DOI: 10.1155/2018/6035868.
  CrossrefPubMedGoogle Scholar
• 29 Bernardi F, Constantino L, Machado R, Petronilho F, Dal-Pizzol F. Plasma nitric oxide, endothelin-1, arginase and superoxide dismutase in pre-eclamptic women. J Obstet Gynaecol Res 2008; 34 (06) 957-963 DOI: 10.1111/j.1447-0756.2008.00860.x.
  CrossrefPubMedGoogle Scholar
• 30 Caldeira-Dias M, Luizon MR, Deffune E, Tanus-Santos JE, Freire PP, Carvalho RF. et al. Preeclamptic plasma stimulates the expression of miRNAs, leading to a decrease in endothelin-1 production in endothelial cells. Pregnancy Hypertens 2018; 12: 75-81 DOI: 10.1016/j.preghy.2018.03.001.
  CrossrefPubMedGoogle Scholar
• 31 Schipper HM, Song W, Tavitian A, Cressatti M. The sinister face of heme oxygenase-1 in brain aging and disease. Prog Neurobiol 2019; 172: 40-70 DOI: 10.1016/j.pneurobio.2018.06.008.
  CrossrefPubMedGoogle Scholar
• 32 Jais A, Einwallner E, Sharif O, Gossens K, Lu TT, Soyal SM. et al. Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man. Cell 2014; 158 (01) 25-40 DOI: 10.1016/j.cell.2014.04.043.
  CrossrefPubMedGoogle Scholar
• 33 Raval CM, Lee PJ. Heme oxygenase-1 in lung disease. Curr Drug Targets 2010; 11 (12) 1532-1540 DOI: 10.2174/1389450111009011532.
  CrossrefPubMedGoogle Scholar
• 34 Song W, Kothari V, Velly AM, Cressatti M, Liberman A, Gornitsky M. et al. Evaluation of salivary heme oxygenase-1 as a potential biomarker of early Parkinson's disease. Mov Disord 2018; 33 (04) 583-591 DOI: 10.1002/mds.27328.
  CrossrefPubMedGoogle Scholar
• 35 Zimmermann MB. The importance of adequate iodine during pregnancy and infancy. World Rev Nutr Diet 2016; 115: 118-124 DOI: 10.1159/000442078.
  CrossrefPubMedGoogle Scholar
• 36 Mills JL, Buck Louis GM, Kannan K, Weck J, Wan Y, Maisog J. et al. Delayed conception in women with low-urinary iodine concentrations: a population-based prospective cohort study. Hum Reprod 2018; 33 (03) 426-433 DOI: 10.1093/humrep/dex379.
  CrossrefPubMedGoogle Scholar
• 37 Mioto VCB, Monteiro ACCNG, de Camargo RYA, Borel AR, Catarino RM, Kobayashi S. et al. High prevalence of iodine deficiency in pregnant women living in adequate iodine area. Endocr Connect 2018; 7 (05) 762-767 DOI: 10.1530/EC-18-0131.
  CrossrefPubMedGoogle Scholar
• 38 Ferreira SM, Navarro AM, Magalhães PK, Maciel LM. Iodine insufficiency in pregnant women from the State of São Paulo. Arq Bras Endocrinol Metabol 2014; 58 (03) 282-287 DOI: 10.1590/0004-2730000002979.
  CrossrefPubMedGoogle Scholar
• 39 de Lima LF, Barbosa Jr F, Navarro AM. Excess iodinuria in infants and its relation to the iodine in maternal milk. J Trace Elem Med Biol 2013; 27 (03) 221-225 DOI: 10.1016/j.jtemb.2013.01.003.
  CrossrefPubMedGoogle Scholar
• 40 Mill JG, Malta DC, Machado IE, Pate A, Pereira CA, Jaime PC. et al. Estimation of salt intake in the Brazilian population: results from the 2013 National Health Survey. Rev Bras Epidemiol 2019; 22 (22, Suppl 02) E190009-, 2 DOI: 10.1590/1980-549720190009.supl.2.
  CrossrefPubMedGoogle Scholar
• 41 Milczarek M, Stępniak J, Lewiński A, Karbownik-Lewińska M. Potassium iodide, but not potassium iodate, as a potential protective agent against oxidative damage to membrane lipids in porcine thyroid. Thyroid Res 2013; 6 (01) 10 DOI: 10.1186/1756-6614-6-10.
  CrossrefPubMedGoogle Scholar
• 42 Herter-Aeberli I, Cherkaoui M, El Ansari N, Rohner R, Stinca S, Chabaa L. et al. Iodine supplementation decreases hypercholesterolemia in iodine-deficient, overweight women: a randomized controlled trial. J Nutr 2015; 145 (09) 2067-2075 DOI: 10.3945/jn.115.213439.
  CrossrefPubMedGoogle Scholar
• 43 Soriguer F, Gutiérrez-Repiso C, Rubio-Martin E, Linares F, Cardona I, López-Ojeda J. et al. Iodine intakes of 100-300 μg/d do not modify thyroid function and have modest anti-inflammatory effects. Br J Nutr 2011; 105 (12) 1783-1790 DOI: 10.1017/S0007114510005568.
  CrossrefPubMedGoogle Scholar
• 44 Wang Y, Shi D, Chen L. Lipid profile and cytokines in hypertension of pregnancy: A comparison of preeclampsia therapies. J Clin Hypertens (Greenwich) 2018; 20 (02) 394-399 DOI: 10.1111/jch.13161.
  CrossrefPubMedGoogle Scholar
• 45 Brouwers L, van der Meiden-van Roest AJ, Savelkoul C, Vogelvang TE, Lely AT, Franx A. et al. Recurrence of pre-eclampsia and the risk of future hypertension and cardiovascular disease: a systematic review and meta-analysis. BJOG 2018; 125 (13) 1642-1654 DOI: 10.1111/1471-0528.15394.
  CrossrefPubMedGoogle Scholar
• 46 Allain P, Mauras Y, Dougé C, Jaunault L, Delaporte T, Beaugrand C. Determination of iodine and bromine in plasma and urine by inductively coupled plasma mass spectrometry. Analyst (Lond) 1990; 115 (06) 813-815 DOI: 10.1039/an9901500813.
  CrossrefPubMedGoogle Scholar