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Crocin exhibits an antihypertensive effect in a rat model of gestational hypertension and activates the Nrf-2/HO-1 signaling pathway

Hypertension Research volume 44, pages 642–650 (2021)Cite this article

Abstract

Gestational hypertension is a leading cause of both prenatal and maternal mortality and morbidity; however, there have been rather limited advances in the management of gestational hypertension in recent years. There has been evidence supporting the antihypertensive properties of crocin, but the specific mechanism is still unclear. N-Nitro-L-arginine methyl ester (L-NAME) was employed to establish a rat model with a preeclampsia-like phenotype, particularly gestational hypertension. Enzyme-linked immunosorbent assays were conducted to determine the levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1); the levels of the circulating cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α; and oxidative stress factors. Quantitative RT-PCR assays were performed to assess the transcript levels of various cytokines in the placenta, and western blot assays were carried out to evaluate the protein levels of heme oxygenase-1 (HO-1) and nuclear factor-erythroid 2-like 2 (Nrf-2). Treatment with crocin reduced the blood pressure of rats with gestational hypertension, which was accompanied by suppressed circulating levels of PlGF and sFlt-1. Crocin further alleviated the inflammatory signals and oxidative stress in the serum, as well as in placental tissues, in rats with L-NAME-induced hypertension. Crocin treatment also improved pregnancy outcomes in terms of fetal survival, fetal weight, and the fetal/placental weight ratio. Finally, in hypertension elicited by L-NAME, crocin stimulated the placental Nrf-2/HO-1 pathway. Crocin alleviated inflammatory and oxidative stress in placental tissues, thereby protecting against gestational hypertension, one of the major phenotypes of preeclampsia, and activated the Nrf-2/HO-1 pathway.

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References

  1. WHO Recommendations for Prevention and Treatment of Pre-Eclampsia and Eclampsia. Geneva; 2011.

  2. Sharf M, Eibschitz I, Hakim M, Degani S, Rosner B. Is Serum Free Estriol Measurement Essential in the Management of Hypertensive Disorders during Pregnancy. Eur J Obstet Gyn R B. 1984;17:365–75.

    Article  CAS  Google Scholar 

  3. Visintin C, Mugglestone MA, Almerie MQ, Nherera LM, James D, Walkinshaw S, et al. Guidelines Management of hypertensive disorders during pregnancy: summary oif NICE guidance. Brit Med J. 2010;341.

  4. Savitz DA, Danilack VA, Engel SM, Elston B, Lipkind HS. Descriptive epidemiology of chronic hypertension, gestational hypertension, and preeclampsia in New York State, 1995–2004. Matern Child Health J. 2014;18:829–38.

    Article  Google Scholar 

  5. Schneider S, Freerksen N, Maul H, Roehrig S, Fischer B, Hoeft B. Risk groups and maternal-neonatal complications of preeclampsia–current results from the national German Perinatal Quality Registry. J Perinat Med. 2011;39:257–65.

    Article  Google Scholar 

  6. Larcan A, Lambert H, Laprevote MC, Alexandre P. Disseminated intravascular coagulation and acute renal failure in the field of obstetrics. Bibl Anat. 1975;13:347–50.

    CAS  PubMed  Google Scholar 

  7. Rattray DD, O’Connell CM, Baskett TF. Acute disseminated intravascular coagulation in obstetrics: a tertiary centre population review (1980 to 2009). J Obstet Gynaecol Can. 2012;34:341–7.

    Article  Google Scholar 

  8. Draganovic D, Lucic N, Jojic D. Oxidative Stress Marker and Pregnancy Induced Hypertension. Med Arch. 2016;70:437–40.

    Article  Google Scholar 

  9. Harmon AC, Cornelius DC, Amaral LM, Faulkner JL, Cunningham MW Jr, Wallace K, et al. The role of inflammation in the pathology of preeclampsia. Clin Sci (Lond). 2016;130:409–19.

    Article  CAS  Google Scholar 

  10. Matsubara S, Minakami H, Sato I, Saito T. Decrease in cytochrome c oxidase activity detected cytochemically in the placental trophoblast of patients with pre-eclampsia. Placenta. 1997;18:255–9.

    Article  CAS  Google Scholar 

  11. van der Graaf AM, Wiegman MJ, Plosch T, Zeeman GG, van Buiten A, Henning RH, et al. Endothelium-dependent relaxation and angiotensin II sensitivity in experimental preeclampsia. PLoS ONE 2013;8:e79884.

    Article  Google Scholar 

  12. Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharm Toxicol. 2007;47:89–116.

    Article  CAS  Google Scholar 

  13. Kang SJ, You A, Kwak MK. Suppression of Nrf2 signaling by angiotensin II in murine renal epithelial cells. Arch Pharm Res. 2011;34:829–36.

    Article  CAS  Google Scholar 

  14. Itoh K, Mimura J, Yamamoto M. Discovery of the negative regulator of Nrf2, Keap1: a historical overview. Antioxid Redox Signal. 2010;13:1665–78.

    Article  CAS  Google Scholar 

  15. Kweider N, Huppertz B, Kadyrov M, Rath W, Pufe T, Wruck CJ. A possible protective role of Nrf2 in preeclampsia. Ann Anat. 2014;196:268–77.

    Article  Google Scholar 

  16. Rahaiee S, Moini S, Hashemi M, Shojaosadati SA. Evaluation of antioxidant activities of bioactive compounds and various extracts obtained from saffron (Crocus sativus L.): a review. J Food Sci Technol. 2015;52:1881–8.

    Article  CAS  Google Scholar 

  17. Imenshahidi M, Hosseinzadeh H, Javadpour Y. Hypotensive effect of aqueous saffron extract (Crocus sativus L.) and its constituents, safranal and crocin, in normotensive and hypertensive rats. Phytother Res. 2010;24:990–4.

    Article  CAS  Google Scholar 

  18. Imenshahidi M, Razavi BM, Faal A, Gholampoor A, Mousavi SM, Hosseinzadeh H. The Effect of Chronic Administration of Saffron (Crocus sativus) Stigma Aqueous Extract on Systolic Blood Pressure in Rats. Jundishapur J Nat Pharm Prod. 2013;8:175–9.

    Article  Google Scholar 

  19. Imenshahidi M, Razavi BM, Faal A, Gholampoor A, Mousavi SM, Hosseinzadeh H. Effects of chronic crocin treatment on desoxycorticosterone acetate (doca)-salt hypertensive rats. Iran J Basic Med Sci. 2014;17:9–13.

    PubMed  PubMed Central  Google Scholar 

  20. Shafei MN, Faramarzi A, Khajavi Rad A, Anaeigoudari A. Crocin prevents acute angiotensin II-induced hypertension in anesthetized rats. Avicenna J Phytomed. 2017;7:345–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Kim JH, Park GY, Bang SY, Park SY, Bae SK, Kim Y. Crocin suppresses LPS-stimulated expression of inducible nitric oxide synthase by upregulation of heme oxygenase-1 via calcium/calmodulin-dependent protein kinase 4. Mediators Inflamm. 2014;2014:728709.

    PubMed  PubMed Central  Google Scholar 

  22. Godugu C, Pasari LP, Khurana A, Anchi P, Saifi MA, Bansod SP, et al. Crocin, an active constituent of Crocus sativus ameliorates cerulein induced pancreatic inflammation and oxidative stress. Phytother Res. 2020;34:825–35.

    Article  CAS  Google Scholar 

  23. Khodir AE, Said E, Atif H, ElKashef HA, Salem HA. Targeting Nrf2/HO-1 signaling by crocin: Role in attenuation of AA-induced ulcerative colitis in rats. Biomed Pharmacother. 2019;110:389–99.

    Article  CAS  Google Scholar 

  24. 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:e111902.

    Article  Google Scholar 

  25. Wang Y, Huang M, Yang X, Yang Z, Li L, Mei J. Supplementing punicalagin reduces oxidative stress markers and restores angiogenic balance in a rat model of pregnancy-induced hypertension. Korean J Physiol Pharmacol. 2018;22:409–17.

    Article  Google Scholar 

  26. Armaly Z, Zaher M, Knaneh S, Abassi Z. [Preeclampsia: Pathogenesis and Mechanisms Based Therapeutic Approaches]. Harefuah. 2019;158:742–7.

    PubMed  Google Scholar 

  27. Moradi MT, Rahimi Z, Vaisi-Raygani A. New insight into the role of long non-coding RNAs in the pathogenesis of preeclampsia. Hypertens Pregnancy. 2019;38:41–51.

    Article  CAS  Google Scholar 

  28. Lv X, Li X, Dai X, Liu M, Wu C, Song W, et al. Investigation heme oxygenase-1 polymorphism with the pathogenesis of preeclampsia. Clin Exp Hypertens. 2020;42:167–70.

    Article  Google Scholar 

  29. Kara AE, Guney G, Tokmak A, Ozaksit G. The role of inflammatory markers hs-CRP, sialic acid, and IL-6 in the pathogenesis of preeclampsia and intrauterine growth restriction. Eur Cytokine Netw. 2019;30:29–33.

    CAS  PubMed  Google Scholar 

  30. Matsubara K, Higaki T, Matsubara Y, Nawa A. Nitric oxide and reactive oxygen species in the pathogenesis of preeclampsia. Int J Mol Sci. 2015;16:4600–14.

    Article  CAS  Google Scholar 

  31. Matsubara K, Matsubara Y, Hyodo S, Katayama T, Ito M. Role of nitric oxide and reactive oxygen species in the pathogenesis of preeclampsia. J Obstet Gynaecol Res. 2010;36:239–47.

    Article  CAS  Google Scholar 

  32. Sircar M, Thadhani R, Karumanchi SA. Pathogenesis of preeclampsia. Curr Opin Nephrol Hypertens. 2015;24:131–8.

    Article  CAS  Google Scholar 

  33. Williams PJ, Searle RF, Robson SC, Innes BA, Bulmer JN. Decidual leucocyte populations in early to late gestation normal human pregnancy. J Reprod Immunol. 2009;82:24–31.

    Article  CAS  Google Scholar 

  34. Chen S, Sun P, Zhao X, Yi R, Qian J, Shi Y, et al. Gardenia jasminoides has therapeutic effects on LNNAinduced hypertension in vivo. Mol Med Rep. 2017;15:4360–73.

    Article  CAS  Google Scholar 

  35. Raji M, Chen Z. Effects of abiotic elicitors on the production of bioactive flavonols in Emilia sonchifolia. STEMedicine. 2020;1:e33.

    Article  Google Scholar 

  36. 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;73:3221–47.

    Article  CAS  Google Scholar 

  37. Ding C, Zou Q, Wu Y, Lu J, Qian C, Li H, et al. EGF released from human placental mesenchymal stem cells improves premature ovarian insufficiency via NRF2/HO-1 activation. Aging (Albany NY). 2020;12:2992–3009.

    Article  CAS  Google Scholar 

  38. Chigusa Y, Tatsumi K, Kondoh E, Fujita K, Nishimura F, Mogami H, 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.

    Article  CAS  Google Scholar 

  39. Talaei A, Hassanpour Moghadam M, Sajadi Tabassi SA, Mohajeri SA. Crocin, the main active saffron constituent, as an adjunctive treatment in major depressive disorder: a randomized, double-blind, placebo-controlled, pilot clinical trial. J Affect Disord. 2015;174:51–6.

    Article  CAS  Google Scholar 

  40. Sepahi S, Mohajeri SA, Hosseini SM, Khodaverdi E, Shoeibi N, Namdari M, et al. Effects of Crocin on Diabetic Maculopathy: A Placebo-Controlled Randomized Clinical Trial. Am J Ophthalmol. 2018;190:89–98.

    Article  CAS  Google Scholar 

  41. Ghaderi A, Rasouli-Azad M, Vahed N, Banafshe HR, Soleimani A, Omidi A, et al. Clinical and metabolic responses to crocin in patients under methadone maintenance treatment: A randomized clinical trial. Phytother Res. 2019;33:2714–25.

    Article  CAS  Google Scholar 

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Funding

The study was supported by the Quanzhou Science and Technology Plan Project (2020N022s).

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  1. These authors contributed equally: Xuan Chen, Jingying Huang

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Quanzhou First Hospital Affiliated to Fujian Medical University, No. 250 East Street, Quanzhou, 362000, Fujian, China

    Xuan Chen, Jingying Huang, Yuchun Lv & Jinghong Rao

  2. Department of Clinical Medicine, Quanzhou Medical College, Quanzhou, 362011, Fujian, China

    Youfang Chen

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Chen, X., Huang, J., Lv, Y. et al. Crocin exhibits an antihypertensive effect in a rat model of gestational hypertension and activates the Nrf-2/HO-1 signaling pathway. Hypertens Res 44, 642–650 (2021). https://doi.org/10.1038/s41440-020-00609-7

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