Startseite Selective estrogen receptor α and β antagonist aggravate cardiovascular dysfunction in type 2 diabetic ovariectomized female rats
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Selective estrogen receptor α and β antagonist aggravate cardiovascular dysfunction in type 2 diabetic ovariectomized female rats

  • Hossein Azizian , Zeinab Farhadi und Mohammad Khaksari EMAIL logo
Veröffentlicht/Copyright: 6. Mai 2022
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Hormone Molecular Biology and Clinical Investigation
Aus der Zeitschrift Hormone Molecular Biology and Clinical Investigation Band 43 Heft 4

Abstract

Objectives

Type 2 diabetes (T2D) is a major risk factor for cardiovascular disorders (CVD), characterized by pathological diastolic as well as systolic dysfunction, ventricular dilation, and cardiomyocyte hypertrophy. CVD is the main cause of death in postmenopausal women. Estradiol (E2) has protective effects on cardiovascular function. The biological effects of E2 are mainly mediated by classical estrogen receptors (ERs). The present study aimed to investigate the cardioprotective effects of classical ERs in ovariectomized (OVX) diabetic female rats.

Methods

T2D was induced in female rats by high-fat diet feeding along with a low dose of streptozotocin. Then diabetic animals were divided into eight groups: Sham-control, OVX, OVX + Vehicle (Veh), OVX + E2, OVX + E2 + MPP (ERα antagonist), OVX + E2 + PHTPP (ERβ antagonist), OVX + E2 + Veh, OVX + E2 + MPP + PHTPP. Animals received E2, MPP, and PHTPP every four days for 28 days. At the end blood was collected, serum separated, and used for biochemical parameters. Heart tissue was used for cardiac angiotensin II and cytokines measurement.

Results

E2 treatment improved the metabolic disorders caused by T2D, and its receptor antagonists intensified the effects of T2D on the metabolic status. Also, E2 therapy decreased cardiac inflammatory cytokines, and MPP and PHTPP increased cardiac inflammation by increasing TNF-α and IL-6 and decreasing IL-10.

Conclusions

Classical ERs have protective effects on diabetic hearts by improving the metabolic status and inflammatory balance.

Keywords: cardiovascular; cytokines; estrogen; MPP and PHTPP; type 2 diabetes
Corresponding author: Mohammad Khaksari, Ph.D, Professor of Physiology, Endocrinology and Metabolism Research, and Physiology Research Centers, Kerman University of Medical Sciences, Kerman, Iran, and Department of Physiology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran, E-mail: ,

Acknowledgments

The authors are grateful to Mr. Yaser Masoumi‐Ardakani and Payam Ghotbi for technical assistance.

  1. Research funding: The authors state that no funding was involved.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: The authors declare that there is no conflict of interests.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: All procedures were approved by the ethical committee (Permission No: 95/105KA). Care was taken to avoid stressful conditions, and all procedures were performed between 9 and 11 a.m.

References

1. Kannel, WB, McGee, DL. Diabetes and cardiovascular disease: the Framingham study. JAMA 1979;241:2035–8. https://doi.org/10.1001/jama.1979.03290450033020.Suche in Google Scholar

2. Barouch, LA, Gao, D, Chen, L, Miller, KL, Xu, W, Phan, AC, et al.. Cardiac myocyte apoptosis is associated with increased DNA damage and decreased survival in murine models of obesity. Circ Res 2006;98:119–24. https://doi.org/10.1161/01.res.0000199348.10580.1d.Suche in Google Scholar

3. Kernohan, A, Sattar, N, Hilditch, T, Cleland, S, Small, M, Lumsden, M, et al.. Effects of low‐dose continuous combined hormone replacement therapy on glucose homeostasis and markers of cardiovascular risk in women with type 2 diabetes. Clin. Endocrinol. 2007;66:27–34. https://doi.org/10.1111/j.1365-2265.2006.02679.x.Suche in Google Scholar PubMed

4. Kanaya, AM, Herrington, D, Vittinghoff, E, Lin, F, Grady, D, Bittner, V, et al.. Glycemic effects of postmenopausal hormone therapy: the heart and estrogen/progestin replacement study: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003;138:1–9. https://doi.org/10.7326/0003-4819-138-1-200301070-00005.Suche in Google Scholar PubMed

5. Saengsirisuwan, V, Pongseeda, S, Prasannarong, M, Vichaiwong, K, Toskulkao, C. Modulation of insulin resistance in ovariectomized rats by endurance exercise training and estrogen replacement. Metabolism 2009;58:38–47. https://doi.org/10.1016/j.metabol.2008.08.004.Suche in Google Scholar PubMed

6. Bryzgalova, G, Lundholm, L, Portwood, N, Gustafsson, J-A, Khan, A, Efendic, S, et al.. Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet-fed mice. Am J Physiol Endocrinol Metab 2008;295:E904–12. https://doi.org/10.1152/ajpendo.90248.2008.Suche in Google Scholar PubMed PubMed Central

7. Lontchi-Yimagou, E, Sobngwi, E, Matsha, TE, Kengne, AP. Diabetes mellitus and inflammation. Curr Diabetes Rep 2013;13:435–44. https://doi.org/10.1007/s11892-013-0375-y.Suche in Google Scholar PubMed

8. Minamino, T, Orimo, M, Shimizu, I, Kunieda, T, Yokoyama, M, Ito, T, et al.. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med 2009;15:1082–7. https://doi.org/10.1038/nm.2014.Suche in Google Scholar PubMed

9. Kengne, AP, Czernichow, S, Stamatakis, E, Hamer, M, Batty, GD. Fibrinogen and future cardiovascular disease in people with diabetes: aetiological associations and risk prediction using individual participant data from nine community-based prospective cohort studies. Diabetes Vasc Dis Res 2013;10:143–51. https://doi.org/10.1177/1479164112451588.Suche in Google Scholar PubMed

10. Dandona, P, Aljada, A, Bandyopadhyay, A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 2004;25:4–7. https://doi.org/10.1016/j.it.2003.10.013.Suche in Google Scholar PubMed

11. Khaksari, M, Soltani, Z, Shahrokhi, N. Effects of Female Sex Steroids Administration on Pathophysiologic Mechanisms in Traumatic Brain Injury. Translational stroke research 2018;9:393–416. https://doi.org/10.1007/s12975-017-0588-5.Suche in Google Scholar PubMed

12. Libby, P, Ridker, PM, Maseri, A. Inflammation and atherosclerosis. Circulation 2002;105:1135–43. https://doi.org/10.1161/hc0902.104353.Suche in Google Scholar PubMed

13. Tuttle, HA, Davis-Gorman, G, Goldman, S, Copeland, JG, McDonagh, PF. Proinflammatory cytokines are increased in type 2 diabetic women with cardiovascular disease. J Diabetes Complicat 2004;18:343–51. https://doi.org/10.1016/s1056-8727(03)00088-6.Suche in Google Scholar PubMed

14. Mosca, L, Collins, P, Herrington, DM, Mendelsohn, ME, Pasternak, RC, Robertson, RM, et al.. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 2001;104:499–503. https://doi.org/10.1161/hc2901.092200.Suche in Google Scholar PubMed

15. Curato, C, Slavic, S, Dong, J, Skorska, A, Altarche-Xifró, W, Miteva, K, et al.. Identification of noncytotoxic and IL-10–producing CD8+ AT2R+ T cell population in response to ischemic heart injury. J Immunol 2010;185:6286–93. https://doi.org/10.4049/jimmunol.0903681.Suche in Google Scholar PubMed

16. Knowlton, AA, Lee, A. Estrogen and the cardiovascular system. Pharmacol Ther 2012;135:54–70. https://doi.org/10.1016/j.pharmthera.2012.03.007.Suche in Google Scholar PubMed PubMed Central

17. Murphy, E. Estrogen signaling and cardiovascular disease. Circ Res 2011;109:687–96. https://doi.org/10.1161/circresaha.110.236687.Suche in Google Scholar

18. Wang, M, Wang, Y, Weil, B, Abarbanell, A, Herrmann, J, Tan, J, et al.. Estrogen receptor β mediates increased activation of PI3K/Akt signaling and improved myocardial function in female hearts following acute ischemia. Am J Physiol Regul Integr Comp Physiol 2009;296:R972–8. https://doi.org/10.1152/ajpregu.00045.2009.Suche in Google Scholar PubMed PubMed Central

19. Jiang, C, Wang, J, Li, X, Liu, C, Chen, N, Hao, Y. Progesterone exerts neuroprotective effects by inhibiting inflammatory response after stroke. Inflamm Res 2009;58:619–24. https://doi.org/10.1007/s00011-009-0032-8.Suche in Google Scholar PubMed

20. Khaksari, M, Keshavarzi, Z, Gholamhoseinian, A, Bibak, B. The effect of female sexual hormones on the intestinal and serum cytokine response after traumatic brain injury: different roles for estrogen receptor subtypes. Can J Physiol Pharmacol 2013;91:700–7. https://doi.org/10.1139/cjpp-2012-0359.Suche in Google Scholar PubMed

21. Khaksari, M, Hajializadeh, Z, Shahrokhi, N, Esmaeili-Mahani, S. Changes in the gene expression of estrogen receptors involved in the protective effect of estrogen in rat’s trumatic brain injury. Brain Res 2015;1618:1–8. https://doi.org/10.1016/j.brainres.2015.05.017.Suche in Google Scholar PubMed

22. Farhadi, Z, Khaksari, M, Azizian, H, Mortazaeizadeh, A, Shabani, M, Shahrokhi, N. Beneficial effects of tamoxifen on leptin sensitivity in young mice fed a high fat diet: role of estrogen receptor alpha and cytokines. Life Sci 2020;246:117384. https://doi.org/10.1016/j.lfs.2020.117384.Suche in Google Scholar PubMed

23. Azizian, H, Khaksari, M, Asadikaram, G, Esmailidehaj, M, Shahrokhi, N. Progesterone eliminates 17β-estradiol-Mediated cardioprotection against diabetic cardiovascular dysfunction in ovariectomized rats. Biomed J 2021;44:461–70. https://doi.org/10.1016/j.bj.2020.03.002.Suche in Google Scholar PubMed PubMed Central

24. Naderi, V, Khaksari, M, Abbasi, R, Maghool, F. Estrogen provides neuroprotection against brain edema and blood brain barrier disruption through both estrogen receptors α and β following traumatic brain injury. Iran J Basic Med Sci 2015;18:138.Suche in Google Scholar

25. Ebrahimi, MN, Khaksari, M, Sepehri, G, Karam, GA, Raji-Amirhasani, A, Azizian, H. The effects of alone and combination tamoxifen, raloxifene and estrogen on lipid profile and atherogenic index of ovariectomized type 2 diabetic rats. Life Sci 2020;263:118573. https://doi.org/10.1016/j.lfs.2020.118573.Suche in Google Scholar PubMed

26. Bansal, S, Chopra, K. Distinct role of estrogen receptor-alpha and beta on postmenopausal diabetes-induced vascular dysfunction. Gen Comp Endocrinol 2014;206:51–9. https://doi.org/10.1016/j.ygcen.2014.06.013.Suche in Google Scholar PubMed

27. Farhadi, Z, Khaksari, M, Azizian, H, Dabiri, S, Fallah, H, Nozari, M. Aging is associated with loss of beneficial effects of estrogen on leptin responsiveness in mice fed high fat diet: role of estrogen receptor α and cytokines. Mech Ageing Dev 2020;186:111198. https://doi.org/10.1016/j.mad.2019.111198.Suche in Google Scholar PubMed

28. Roesch, DM. Effects of selective estrogen receptor agonists on food intake and body weight gain in rats. Physiol Behav 2006;87:39–44. https://doi.org/10.1016/j.physbeh.2005.08.035.Suche in Google Scholar PubMed

29. Meyer, MR, Clegg, DJ, Prossnitz, ER, Barton, M. Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors. Acta Physiol 2011;203:259–69. https://doi.org/10.1111/j.1748-1716.2010.02237.x.Suche in Google Scholar PubMed PubMed Central

30. Gupte, AA, Pownall, HJ, Hamilton, DJ. Estrogen: an emerging regulator of insulin action and mitochondrial function. J Diabetes Res 2015;2015. https://doi.org/10.1155/2015/916585.Suche in Google Scholar PubMed PubMed Central

31. Chen, Z, Yuhanna, IS, Galcheva-Gargova, Z, Karas, RH, Mendelsohn, ME, Shaul, PW. Estrogen receptor α mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Investig 1999;103:401–6. https://doi.org/10.1172/jci5347.Suche in Google Scholar PubMed PubMed Central

32. Bansal, S, Chopra, K. Selective ER-α agonist alleviates vascular endothelial dysfunction in ovariectomized type 2 diabetic rats. Mol Cell Endocrinol 2018;460:152–61. https://doi.org/10.1016/j.mce.2017.07.017.Suche in Google Scholar PubMed

33. Salpeter, S, Walsh, J, Ormiston, T, Greyber, E, Buckley, N, Salpeter, E. Meta‐analysis: effect of hormone‐replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metabol 2006;8:538–54. https://doi.org/10.1111/j.1463-1326.2005.00545.x.Suche in Google Scholar PubMed

34. Fielitz, J, Leuschner, M, Zurbrügg, HR, Hannack, B, Pregla, R, Hetzer, R, et al.. Regulation of matrix metalloproteinases and their inhibitors in the left ventricular myocardium of patients with aortic stenosis. J Mol Med 2004;82:809–20. https://doi.org/10.1007/s00109-004-0606-4.Suche in Google Scholar PubMed

35. Khaksari, M, Raji-Amirhasani, A, Bashiri, H, Ebrahimi, MN, Azizian, H, et al.. Protective effects of combining SERMs with estrogen on metabolic parameters in postmenopausal diabetic cardiovascular dysfunction: The role of cytokines and angiotensin II. Steroids 2022;183:109023. https://doi.org/10.1016/j.steroids.2022.109023.Suche in Google Scholar PubMed

36. Shahbazian, M, Jafarynezhad, F, Yadeghari, M, Farhadi, Z, Lotfi Samani, S, Esmailidehaj, M, et al.. The effects of G protein-coupled receptor 30(GPR30) on cardiac glucose metabolism indiabetic ovariectomized female rats. J Basic Clin Physiol Pharmacol 2022. https://doi.org/10.1515/jbcpp-2021-0374.Suche in Google Scholar PubMed

37. Mahmoodzadeh, S, Dworatzek, E, Fritschka, S, Pham, TH, Regitz-Zagrosek, V. 17β-Estradiol inhibits matrix metalloproteinase-2 transcription via MAP kinase in fibroblasts. Cardiovasc Res 2010;85:719–28. https://doi.org/10.1093/cvr/cvp350.Suche in Google Scholar PubMed PubMed Central

38. Fabris, B, Candido, R, Bortoletto, M, Toffoli, B, Bernardi, S, Stebel, M, et al.. Stimulation of cardiac apoptosis in ovariectomized hypertensive rats: potential role of the renin–angiotensin system. J Hypertens 2011;29:273–81. https://doi.org/10.1097/hjh.0b013e328340d0d3.Suche in Google Scholar

39. Al-Trad, B, Ashankyty, IM, Alaraj, M. Progesterone ameliorates diabetic nephropathy in streptozotocin-induced diabetic Rats. Diabetol Metab Syndrome 2015;7:1–13. https://doi.org/10.1186/s13098-015-0097-1.Suche in Google Scholar PubMed PubMed Central

40. Blasko, E, Haskell, CA, Leung, S, Gualtieri, G, Halks-Miller, M, Mahmoudi, M, et al.. Beneficial role of the GPR30 agonist G-1 in an animal model of multiple sclerosis. J Neuroimmunol 2009;214:67–77. https://doi.org/10.1016/j.jneuroim.2009.06.023.Suche in Google Scholar PubMed PubMed Central

41. Esmailidehaj, M, Kuchakzade, F, Rezvani, ME, Farhadi, Z, Esmaeili, H, Azizian, H. 17β-Estradiol improves insulin signalling and insulin resistance in the aged female hearts: role of inflammatory and anti-inflammatory cytokines. Life Sci 2020;253:117673. https://doi.org/10.1016/j.lfs.2020.117673.Suche in Google Scholar PubMed

42. Mofid, B, Soltani, Z, Khaksari, M, Shahrokhi, N, Nakhaee, N, Karamouzian, S, et al.. What are the progesterone-induced changes of the outcome and the serum markers of injury, oxidant activity and inflammation in diffuse axonal injury patients? Int Immunopharmacol 2016;32:103–10. https://doi.org/10.1016/j.intimp.2016.01.015.Suche in Google Scholar PubMed

43. Bolego, C, Cignarella, A, Sanvito, P, Pelosi, V, Pellegatta, F, Puglisi, L, et al.. The acute estrogenic dilation of rat aorta is mediated solely by selective estrogen receptor-α agonists and is abolished by estrogen deprivation. J Pharmacol Exp Therapeut 2005;313:1203–8. https://doi.org/10.1124/jpet.104.082867.Suche in Google Scholar PubMed

Received: 2021-08-07
Revised: 2022-01-03
Accepted: 2022-03-25
Published Online: 2022-05-06

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Letter to the Editor
  3. COVID-19 pandemic: transmission of SARS-CoV-2 in animals, a risk for human beings
  4. Original Articles
  5. Anti Mullerian hormone as a diagnostic tool for polycystic ovary syndrome in women of reproductive age with morbid obesity
  6. Potential tumor marker for hepatocellular carcinoma identification: PI3K and pro-inflammatory cytokines (TGF-β, IL-1, and IL-6)
  7. The investigation of the frequency of the alpha-1-antitrypsin phenotype in patients with liver cirrhosis
  8. Anti-oxidant effect of metformin through AMPK/SIRT1/PGC-1α/SIRT3– independent GPx1 expression in the heart of mice with endometriosis
  9. Hypoxia-inducible factor-1α and ischemia-modified albumin levels in intensive care COVID-19 Patients
  10. Association between TP53 Arg72Pro variant and recurrent pregnancy loss in the Greek population
  11. Selective estrogen receptor α and β antagonist aggravate cardiovascular dysfunction in type 2 diabetic ovariectomized female rats
  12. Adrenocorticotropic hormone (ACTH) level and adrenal deficiency in patients with mucocutaneous pemphigus
  13. The effect of resistance training on serum levels of sex hormones and sperm quality in male rats under X-ray radiation
  14. The effect of high-intensity interval training on serum and adipose tissues vaspin levels in rats fed a high-fat high-sucrose diet
  15. Anti-migratory effect of curcumin on A-549 lung cancer cells via epigenetic reprogramming of RECK/ matrix metalloproteinase axis
  16. Efficacy of rectal progesterone on maternal and neonatal outcomes in pregnant women with Preterm Premature Rupture of membranes: a triple-blind randomised clinical trial
  17. Case Report
  18. Ovarian tissue cryopreservation in Malaysia: a case series
  19. Review Articles
  20. An overview of prognostic value of neurologic and cardiac biomarkers in patients with COVID-19 sequelae
  21. Potential role of melatonin in prevention and treatment of lung cancer
  22. Esketamine–A quick-acting novel antidepressant without the disadvantages of ketamine
https://doi.org/10.1515/hmbci-2021-0073
Schlagwörter für diesen Artikel
cardiovascular; cytokines; estrogen; MPP and PHTPP; type 2 diabetes

Artikel in diesem Heft

  1. Frontmatter
  2. Letter to the Editor
  3. COVID-19 pandemic: transmission of SARS-CoV-2 in animals, a risk for human beings
  4. Original Articles
  5. Anti Mullerian hormone as a diagnostic tool for polycystic ovary syndrome in women of reproductive age with morbid obesity
  6. Potential tumor marker for hepatocellular carcinoma identification: PI3K and pro-inflammatory cytokines (TGF-β, IL-1, and IL-6)
  7. The investigation of the frequency of the alpha-1-antitrypsin phenotype in patients with liver cirrhosis
  8. Anti-oxidant effect of metformin through AMPK/SIRT1/PGC-1α/SIRT3– independent GPx1 expression in the heart of mice with endometriosis
  9. Hypoxia-inducible factor-1α and ischemia-modified albumin levels in intensive care COVID-19 Patients
  10. Association between TP53 Arg72Pro variant and recurrent pregnancy loss in the Greek population
  11. Selective estrogen receptor α and β antagonist aggravate cardiovascular dysfunction in type 2 diabetic ovariectomized female rats
  12. Adrenocorticotropic hormone (ACTH) level and adrenal deficiency in patients with mucocutaneous pemphigus
  13. The effect of resistance training on serum levels of sex hormones and sperm quality in male rats under X-ray radiation
  14. The effect of high-intensity interval training on serum and adipose tissues vaspin levels in rats fed a high-fat high-sucrose diet
  15. Anti-migratory effect of curcumin on A-549 lung cancer cells via epigenetic reprogramming of RECK/ matrix metalloproteinase axis
  16. Efficacy of rectal progesterone on maternal and neonatal outcomes in pregnant women with Preterm Premature Rupture of membranes: a triple-blind randomised clinical trial
  17. Case Report
  18. Ovarian tissue cryopreservation in Malaysia: a case series
  19. Review Articles
  20. An overview of prognostic value of neurologic and cardiac biomarkers in patients with COVID-19 sequelae
  21. Potential role of melatonin in prevention and treatment of lung cancer
  22. Esketamine–A quick-acting novel antidepressant without the disadvantages of ketamine
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