Skip to main content

Advertisement

SpringerLink
Log in

Simvastatin Alleviates Pathology in a Rat Model of Preeclampsia Involving ERK/MAPK Pathway

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Preeclampsia (PE) is a pregnancy-specific condition characterized by new-onset hypertension. There is evidence suggesting that imbalances of angiogenic factors, oxidative stress, and inflammation may be central to the pathogenesis of PE. We sought to investigate whether simvastatin would reduce mean arterial pressure, restore the angiogenic balance, and ameliorate inflammation and oxidative stress in a nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (l-NAME)-induced rat model of PE. We found that blood pressure was significantly increased in the l-NAME group compared to normal pregnant dams (P <.01), and simvastatin reduced this difference. In addition, dams from the l-NAME group showed lower vascular endothelial growth factor (VEGF) and interleukin (IL) 10 levels and higher plasma-soluble FMS-like tyrosine kinase 1 (sFlt-1), tumor necrosis factor a (TNF-α), and oxidative stress marker malondialdehyde (MDA) levels as compared to control dams (P <.01, for all). Interestingly, simvastatin treatment significantly increased VEGF and IL-10 levels while decreased sFlt-1, TNF-α, and MDA levels compared to the untreated l-NAME group. Moreover, simvastatin treatment significantly upregulated protein expression of placental p-extracellular signal-regulated kinase (ERKI), p-p38 mitogen-activated protein kinase (MAPK), p-c-Jun N-terminal kinase, and p-protein kinase B compared to untreated l-NAME control. These results suggest that simvastatin treatment restores angiogenic balance and ameliorates inflammation and oxidative stress in a rat model of PE involving ERK/MAPK pathway.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American college of obstetricians and gynecolo-gists’ task force on hypertension in pregnancy. Obstet Gynecol. 2013;122(5):1122–1131.

    Google Scholar 

  2. Powe CE, Levine RJ, Karumanchi SA. Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease. Circulation. 2011;123(24):2856–2869.

    PubMed  Google Scholar 

  3. Backes CH, Markham K, Moorehead P, Cordero L, Nankervis CA, Giannone PJ. Maternal preeclampsia and neonatal outcomes. J Pregnancy. 2011;2011:214365.

    PubMed  PubMed Central  Google Scholar 

  4. Redman CW, Sargent IL. Latest advances in understanding pre-eclampsia. Science. 2005;308(5728):1592–1594.

    CAS  PubMed  Google Scholar 

  5. Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFltl) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111(5):649–658.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Rana S, Powe CE, Salahuddin S, et al. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation. 2012;125(7):911–919.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Terlecky SR, Terlecky LJ, Giordano CR. Peroxisomes, oxidative stress, and inflammation. World J Biol Chem. 2012;3(5):93–97.

    PubMed  PubMed Central  Google Scholar 

  8. Campos-Canas J, Romo-Palafox I, Albani-Campanario M, Hernandez-Guerrero C. An imbalance in the production of proinflam-matory and anti-inflammatory cytokines is observed in whole blood cultures of preeclamptic women in comparison with healthy pregnant women. Hypertens Pregnancy. 2014;33(2):236–249.

    CAS  PubMed  Google Scholar 

  9. Davila RD, Julian CG, Wilson MJ, et al. Do cytokines contribute to the Andean-associated protection from reduced fetal growth at high altitude? Reprod Sci. 2011;18(1):79–87.

    CAS  PubMed  Google Scholar 

  10. Szarka A, Rigo J Jr, Lazar L, Beko G, Molvarec A. Circulating cytokines, chemokines and adhesion molecules in normal preg-nancy and preeclampsia determined by multiplex suspension array. BMC Immunol. 2010;11:59.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Visser N, van Rijn BB, Rijkers GT, Franx A, Bruinse HW. Inflammatory changes in preeclampsia: current understanding of the maternal innate and adaptive immune response. Obstet Gynecol Surv. 2007;62(3):191–201.

    PubMed  Google Scholar 

  12. Darby MM, Wallace K, Cornelius D, et al. Vitamin D supplemen-tation suppresses hypoxia-stimulated placental cytokine secretion, hypertension and CD4+ T cell stimulation in response to placental ischemia. Med J Obstet Gynecol. 2013;1(2):pii: 1012.

    Google Scholar 

  13. Feng Y, Xu J, Zhou Q, et al. Alpha-1 antitrypsin prevents the development of preeclampsia through suppression of oxidative stress. Front Physiol. 2016;7:176.

    PubMed  PubMed Central  Google Scholar 

  14. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation. 2000;101(2):207–213.

    CAS  PubMed  Google Scholar 

  15. Strazzullo P, Kerry SM, Barbato A, Versiero M, D’Elia L, Cap-puccio FP. Do statins reduce blood pressure?: a meta-analysis of randomized, controlled trials. Hypertension. 2007;49(4):792–798.

    CAS  PubMed  Google Scholar 

  16. Kumasawa K, Ikawa M, Kidoya H, et al. Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model. Proc Natl Acad Sci USA. 2011;108(4):1451–1455.

    CAS  PubMed  Google Scholar 

  17. Singh J, Ahmed A, Girardi G. Role of complement component C1q in the onset of preeclampsia in mice. Hypertension. 2011;58(4):716–724.

    CAS  PubMed  Google Scholar 

  18. Brown C, McFarlane-Anderson N, Alexander-Lindo R, Bishop K, Dasgupta T, McGrowder D. The effects of S-nitrosoglutathione and S-nitroso-N-acetyl-d, l-penicillamine in a rat model of preeclampsia. J Nat Sci Biol Med. 2013;4(2):330–335.

    PubMed  PubMed Central  Google Scholar 

  19. Talebianpoor MS, Mirkhani H. The effect of tempol administra-tion on the aortic contractile responses in rat preeclampsia model. ISRN Pharmacol. 2012;2012:187208.

    PubMed  PubMed Central  Google Scholar 

  20. Kemse NG, Kale AA, Joshi SR. A combined supplementation of omega-3 fatty acids and micronutrients (folic acid, vitamin B12) reduces oxidative stress markers in a rat model of pregnancy induced hypertension. PLoS One. 2014;9(11):e111902.

    PubMed  PubMed Central  Google Scholar 

  21. Chen YQ, Zhao LY, Zhang WZ, Li T. Simvastatin reverses car-diomyocyte hypertrophy via the upregulation of phosphatase and tensin homolog expression. Exp Ther Med. 2015;10(2):797–803.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Gilbert JS, Babcock SA, Granger JP. Hypertension produced by reduced uterine perfusion in pregnant rats is associated with increased soluble fms-like tyrosine kinase-1 expression. Hypertension. 2007;50(6):1142–1147.

    CAS  PubMed  Google Scholar 

  23. Nadeau V, Charron J. Essential role of the ERK/MAPK pathway in blood-placental barrier formation. Development. 2014;141(14):2825–2837.

    CAS  PubMed  Google Scholar 

  24. Brownfoot FC, Tong S, Hannan NJ, et al. Effects of pravastatin on human placenta, endothelium, and women with severe pree-clampsia. Hypertension. 2015;66(3):687–697; discussion 445.

    CAS  PubMed  Google Scholar 

  25. 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(13):1789–1797.

    CAS  PubMed  Google Scholar 

  26. Molvarec A, Szarka A, Walentin S, Szucs E, Nagy B, Rigó J Jr. Circulating angiogenic factors determined by electrochemilumi-nescence immunoassay in relation to the clinical features and laboratory parameters in women with pre-eclampsia. Hypertens Res. 2010;33(9):892–898.

    CAS  PubMed  Google Scholar 

  27. Cardenas-Mondragon MG, Vallejo-Flores G, Delgado-Dominguez J, et al. Preeclampsia is associated with lower production of vascular endothelial growth factor by peripheral blood mononuclear cells. Arch Med Res. 2014;45(7):561–569.

    CAS  PubMed  Google Scholar 

  28. Kulkarni AV, Mehendale SS, Yadav HR, Kilari AS, Taralekar VS, Joshi SR. Circulating angiogenic factors and their association with birth outcomes in preeclampsia. Hypertens Res. 2010;33(6):561–567.

    CAS  PubMed  Google Scholar 

  29. Saad AF, Diken ZM, Kechichian TB, et al. Pravastatin effects on placental prosurvival molecular pathways in a mouse model of preeclampsia. Reprod Sei. 2016;23(11):1593–1599.

    CAS  Google Scholar 

  30. Bayram M, Taskaya A, Bagriacik EU, Ilhan MN, Yaman M. The effect of maternal serum sFAS/sFASL system on etiopathogenesis of preeclampsia and severe preeclampsia [published online August 22, 2012]. J Matern Fetal Neonatal Med.

  31. Sharma A, Satyam A, Sharma JB. Leptin, IL-10 and inflammatory markers (TNF-alpha, IL-6 and IL-8) in pre-eclamptic, normoten-sive pregnant and healthy non-pregnant women. Am J Reprod Immunol. 2007;58(1):21–30.

    CAS  PubMed  Google Scholar 

  32. Orange S, Rasko JE, Thompson JF, et al. Interleukin-10 regulates arterial pressure in early primate pregnancy. Cytokine. 2005;29(4):176–185.

    CAS  PubMed  Google Scholar 

  33. Kalkunte S, Nevers T, Norris WE, Sharma S. Vascular IL-10: a protective role in preeclampsia. J Reprod Immunol. 2011;88(2):165–169.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Lau SY, Guild SJ, Barrett CJ, et al. Tumor necrosis factor-alpha, interleukin-6, and interleukin-10 levels are altered in preeclampsia: a systematic review and meta-analysis. Am J Reprod Immunol. 2013;70(5):412–427.

    CAS  PubMed  Google Scholar 

  35. Afshari JT, Ghomian N, Shameli A, et al. Determination of Interleukin-6 and Tumor Necrosis Factor-alpha concentrations in Iranian-Khorasanian patients with preeclampsia. BMC Preg-nancy Childbirth. 2005;5:14.

    Google Scholar 

  36. Ozler A, Turgut A, Sak ME, et al. Serum levels of neopterin, tumor necrosis factor-alpha and Interleukin-6 in preeclampsia: relationship with disease severity. Eur Rev Med Pharmacol Sci. 2012;16(12):1707–1712.

    CAS  PubMed  Google Scholar 

  37. Shiraishi M, Haruna M, Matsuzaki M, et al. Relationship between plasma total homocysteine level and dietary caffeine and vitamin B6 intakes in pregnant women. Nurs Health Sci. 2014;16(2):164–170.

    PubMed  Google Scholar 

  38. Pimentel AM, Pereira NR, Costa CA, et al. L-arginine-nitric oxide pathway and oxidative stress in plasma and platelets of patients with pre-eclampsia. Hypertens Res. 2013;36(9):783–788.

    CAS  PubMed  Google Scholar 

  39. Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced can-cer. Chem Biol Interact. 2006;160(1):1–40.

    CAS  PubMed  Google Scholar 

  40. Hopkins MH, Fedirko V, Jones DP, Terry PD, Bostick RM. Antioxidant micronutrients and biomarkers of oxidative stress and inflammation in colorectal adenoma patients: results from a ran-domized, controlled clinical trial. Cancer Epidemiol Biomarkers Prev. 2010;19(3):850–858.

    CAS  PubMed  Google Scholar 

  41. Torry DS, Mukherjea D, Arroyo J, Torry RJ. Expression and function of placenta growth factor: implications for abnormal placentation. J Soc Gynecol Investig. 2003;10(4):178–188.

    CAS  PubMed  Google Scholar 

  42. Shi GX, Jin L, Andres DA. A rit GTPase-p38 mitogen-activated protein kinase survival pathway confers resistance to cellular stress. Mol Cell Biol. 2011;31(10):1938–1948.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Yano M, Matsumura T, Senokuchi T, et al. Statins activate per-oxisome proliferator-activated receptor gamma through extracel-lular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages. Circ Res. 2007;100(10):1442–1451.

    CAS  PubMed  Google Scholar 

  44. Takenouchi Y, Kobayashi T, Matsumoto T, Kamata K. Possible involvement of Akt activity in endothelial dysfunction in type 2 diabetic mice. J Pharmacol Sci. 2008;106(4):600–608.

    CAS  PubMed  Google Scholar 

  45. Shiota M, Hikita Y, Kawamoto Y, et al. Pravastatin-induced proangiogenic effects depend upon extracellular FGF-2. J Cell Mol Med. 2012;16(9):2001–2009.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Chen JC, Huang KC, Lin WW. HMG-CoA reductase inhibitors upregulate heme oxygenase-1 expression in murine RAW264.7 macrophages via ERK, p38 MAPK and protein kinase G path-ways. Cell Signal. 2006;18:32–39.

    CAS  PubMed  Google Scholar 

  47. Hinkelmann U, Grosser N, Erdmann K, Schröder H, Immenschuh S. Simvastatin-dependent up-regulation of heme oxygenase-1 via mRNA stabilization in human endothelial cells. Eur J Pharm Sci. 2010;41(1):118–124.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics, Cangzhou City Central Hospital, Cangzhou, 061001, China

    Xiujuan Dong MD & Dandan Shi MD

Authors
  1. Xiujuan Dong MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dandan Shi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiujuan Dong MD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dong, X., Shi, D. Simvastatin Alleviates Pathology in a Rat Model of Preeclampsia Involving ERK/MAPK Pathway. Reprod. Sci. 24, 1053–1061 (2017). https://doi.org/10.1177/1933719116678693

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719116678693

Keywords

Search

Navigation