Skip to main content

Sex Differences in Animal Models for Cardiovascular Diseases and the Role of Estrogen

  • Chapter
  • First Online:
Book cover Sex and Gender Differences in Pharmacology

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 214))

Abstract

Clinical findings show sex differences in the manifestation of a number of cardiovascular diseases (CVD). However, the underlying molecular mechanisms are incompletely understood. Multiple animal models suggest sex differences in the manifestation of CVD, and provide strong experimental evidence that different major pathways are regulated in a sex-specific manner. In most animal studies females display a lower mortality, less severe hypertrophy, and better preserved cardiac function compared with male counterparts. The data support the hypothesis that female sex and/or the sex hormone estrogen (17β-estradiol; E2) may contribute to the sexual dimorphism in the heart and to a better outcome of cardiac diseases in females. To improve our understanding of the sex-based molecular and cellular mechanisms of CVD and to develop new therapeutic strategies, the use of appropriate animal models is essential. This review highlights recent findings from animal models relevant for studying the mechanisms of sexual dimorphisms in the healthy and diseased heart, focusing on physiological hypertrophy (exercise), pathological hypertrophy (volume and pressure overload induced hypertrophy), and heart failure (myocardial infarction). Furthermore, the potential effects of E2 in these models will be discussed.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

CVD:

Cardiovascular disease

MH:

Myocardial hypertrophy

I/R:

Ischemia/reperfusion

E2:

Estrogen (17β-estradiol)

ER:

Estrogen receptor

References

  • Angele MK, Nitsch S, Knoferl MW, Ayala A, Angele P, Schildberg FW, Jauch KW, Chaudry IH (2003) Sex-specific p38 MAP kinase activation following trauma-hemorrhage: involvement of testosterone and estradiol. Am J Physiol Endocrinol Metab 285:E189–E196

    PubMed  CAS  Google Scholar 

  • Antos CL, McKinsey TA, Frey N, Kutschke W, McAnally J, Shelton JM, Richardson JA, Hill JA, Olson EN (2002) Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A 99:907–912

    Article  PubMed  CAS  Google Scholar 

  • Babiker FA, De Windt LJ, van Eickels M, Thijssen V, Bronsaer RJ, Grohe C, van Bilsen M, Doevendans PA (2004) 17beta-estradiol antagonizes cardiomyocyte hypertrophy by autocrine/paracrine stimulation of a guanylyl cyclase A receptor-cyclic guanosine monophosphate-dependent protein kinase pathway. Circulation 109:269–276

    Article  PubMed  CAS  Google Scholar 

  • Babiker FA, Lips D, Meyer R, Delvaux E, Zandberg P, Janssen B, van Eys G, Grohe C, Doevendans PA (2006) Estrogen receptor beta protects the murine heart against left ventricular hypertrophy. Arterioscler Thromb Vasc Biol 26(7):1524–1530

    Article  PubMed  CAS  Google Scholar 

  • Babiker FA, Lips DJ, Delvaux E, Zandberg P, Janssen BJ, Prinzen F, van Eys G, Grohe C, Doevendans PA (2007) Oestrogen modulates cardiac ischaemic remodelling through oestrogen receptor-specific mechanisms. Acta Physiol (Oxf) 189:23–31

    Article  CAS  Google Scholar 

  • Bae S, Zhang L (2005) Gender differences in cardioprotection against ischemia/reperfusion injury in adult rat hearts: focus on Akt and protein kinase C signaling. J Pharmacol Exp Ther 315:1125–1135

    Article  PubMed  CAS  Google Scholar 

  • Bell JR, Porrello ER, Huggins CE, Harrap SB, Delbridge LM (2008) The intrinsic resistance of female hearts to an ischemic insult is abrogated in primary cardiac hypertrophy. Am J Physiol Heart Circ Physiol 294:H1514–H1522

    Article  PubMed  CAS  Google Scholar 

  • Bernardo BC, Weeks KL, Pretorius L, McMullen JR (2010) Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther 128:191–227

    Article  PubMed  CAS  Google Scholar 

  • Booth EA, Marchesi M, Kilbourne EJ, Lucchesi BR (2003) 17Beta-estradiol as a receptor-mediated cardioprotective agent. J Pharmacol Exp Ther 307:395–401

    Article  PubMed  CAS  Google Scholar 

  • Booth EA, Obeid NR, Lucchesi BR (2005) Activation of estrogen receptor-alpha protects the in vivo rabbit heart from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 289:H2039–H2047

    Article  PubMed  CAS  Google Scholar 

  • Booth EA, Marchesi M, Knittel AK, Kilbourne EJ, Lucchesi BR (2007) The pathway-selective estrogen receptor ligand WAY-169916 reduces infarct size after myocardial ischemia and reperfusion by an estrogen receptor dependent mechanism. J Cardiovasc Pharmacol 49:401–407

    Article  PubMed  CAS  Google Scholar 

  • Bouma W, Noma M, Kanemoto S, Matsubara M, Leshnower BG, Hinmon R, Gorman JH III, Gorman RC (2010) Sex-related resistance to myocardial ischemia-reperfusion injury is associated with high constitutive ARC expression. Am J Physiol Heart Circ Physiol 298:H1510–H1517

    Article  PubMed  CAS  Google Scholar 

  • Brower GL, Gardner JD, Janicki JS (2003) Gender mediated cardiac protection from adverse ventricular remodeling is abolished by ovariectomy. Mol Cell Biochem 251:89–95

    Article  PubMed  CAS  Google Scholar 

  • Brown DA, Lynch JM, Armstrong CJ, Caruso NM, Ehlers LB, Johnson MS, Moore RL (2005) Susceptibility of the heart to ischaemia-reperfusion injury and exercise-induced cardioprotection are sex-dependent in the rat. J Physiol 564:619–630

    Article  PubMed  CAS  Google Scholar 

  • Camper-Kirby D, Welch S, Walker A, Shiraishi I, Setchell KD, Schaefer E, Kajstura J, Anversa P, Sussman MA (2001) Myocardial Akt activation and gender: increased nuclear activity in females versus males. Circ Res 88:1020–1027

    Article  PubMed  CAS  Google Scholar 

  • Carroll JD, Carroll EP, Feldman T, Ward DM, Lang RM, McGaughey D, Karp RB (1992) Sex-associated differences in left ventricular function in aortic stenosis of the elderly. Circulation 86:1099–1107

    Article  PubMed  CAS  Google Scholar 

  • Cavasin MA, Tao Z, Menon S, Yang XP (2004) Gender differences in cardiac function during early remodeling after acute myocardial infarction in mice. Life Sci 75:2181–2192

    Article  PubMed  CAS  Google Scholar 

  • Chu SH, Goldspink P, Kowalski J, Beck J, Schwertz DW (2006) Effect of estrogen on calcium-handling proteins, beta-adrenergic receptors, and function in rat heart. Life Sci 79:1257–1267

    Article  PubMed  CAS  Google Scholar 

  • Cross HR, Murphy E, Steenbergen C (2002) Ca(2+) loading and adrenergic stimulation reveal male/female differences in susceptibility to ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 283:H481–H489

    PubMed  CAS  Google Scholar 

  • Cross HR, Kranias EG, Murphy E, Steenbergen C (2003) Ablation of PLB exacerbates ischemic injury to a lesser extent in female than male mice: protective role of NO. Am J Physiol Heart Circ Physiol 284:H683–H690

    PubMed  CAS  Google Scholar 

  • Cui YH, Tan Z, Fu XD, Xiang QL, Xu JW, Wang TH (2011) 17beta-estradiol attenuates pressure overload-induced myocardial hypertrophy through regulating caveolin-3 protein in ovariectomized female rats. Mol Biol Rep 38:4885–4892

    Article  PubMed  CAS  Google Scholar 

  • Czubryt MP, McAnally J, Fishman GI, Olson EN (2003) Regulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha ) and mitochondrial function by MEF2 and HDAC5. Proc Natl Acad Sci U S A 100:1711–1716

    Article  PubMed  CAS  Google Scholar 

  • Dash R, Schmidt AG, Pathak A, Gerst MJ, Biniakiewicz D, Kadambi VJ, Hoit BD, Abraham WT, Kranias EG (2003) Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy. Cardiovasc Res 57:704–714

    Article  PubMed  CAS  Google Scholar 

  • De Bono JP, Adlam D, Paterson DJ, Channon KM (2006) Novel quantitative phenotypes of exercise training in mouse models. Am J Physiol Regul Integr Comp Physiol 290:R926–R934

    Article  PubMed  CAS  Google Scholar 

  • DeBosch B, Treskov I, Lupu TS, Weinheimer C, Kovacs A, Courtois M, Muslin AJ (2006) Akt1 is required for physiological cardiac growth. Circulation 113:2097–2104

    Article  PubMed  CAS  Google Scholar 

  • Dent MR, Tappia PS, Dhalla NS (2010) Gender differences in apoptotic signaling in heart failure due to volume overload. Apoptosis 15:499–510

    Article  PubMed  Google Scholar 

  • Dent MR, Tappia PS, Dhalla NS (2011) Gender differences in beta-adrenoceptor system in cardiac hypertrophy due to arteriovenous fistula. J Cell Physiol 226:181–186

    Article  PubMed  CAS  Google Scholar 

  • Djouadi F, Weinheimer CJ, Saffitz JE, Pitchford C, Bastin J, Gonzalez FJ, Kelly DP (1998) A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor alpha-deficient mice. J Clin Invest 102:1083–1091

    Article  PubMed  CAS  Google Scholar 

  • Douglas PS, Katz SE, Weinberg EO, Chen MH, Bishop SP, Lorell BH (1998) Hypertrophic remodeling: gender differences in the early response to left ventricular pressure overload. J Am Coll Cardiol 32:1118–1125

    Article  PubMed  CAS  Google Scholar 

  • Du XJ (2004) Gender modulates cardiac phenotype development in genetically modified mice. Cardiovasc Res 63:510–519

    Article  PubMed  CAS  Google Scholar 

  • Dubey RK, Jackson EK, Keller PJ, Imthurn B, Rosselli M (2001) Estradiol metabolites inhibit endothelin synthesis by an estrogen receptor-independent mechanism. Hypertension 37:640–644

    Article  PubMed  CAS  Google Scholar 

  • Fang L, Gao XM, Moore XL, Kiriazis H, Su Y, Ming Z, Lim YL, Dart AM, Du XJ (2007) Differences in inflammation, MMP activation and collagen damage account for gender difference in murine cardiac rupture following myocardial infarction. J Mol Cell Cardiol 43:535–544

    Article  PubMed  CAS  Google Scholar 

  • Fliegner D, Schubert C, Penkalla A, Witt H, Kararigas G, Dworatzek E, Staub E, Martus P, Ruiz Noppinger P, Kintscher U, Gustafsson JA, Regitz-Zagrosek V (2010) Female sex and estrogen receptor-beta attenuate cardiac remodeling and apoptosis in pressure overload. Am J Physiol Regul Integr Comp Physiol 298:R1597–R1606

    Article  PubMed  CAS  Google Scholar 

  • Foryst-Ludwig A, Kintscher U (2010) Metabolic impact of estrogen signalling through ERalpha and ERbeta. J Steroid Biochem Mol Biol 122:74–81

    Article  PubMed  CAS  Google Scholar 

  • Foryst-Ludwig A, Kreissl MC, Sprang C, Thalke B, Bohm C, Benz V, Gurgen D, Dragun D, Schubert C, Mai K, Stawowy P, Spranger J, Regitz-Zagrosek V, Unger T, Kintscher U (2011) Sex differences in physiological cardiac hypertrophy are associated with exercise-mediated changes in energy substrate availability. Am J Physiol Heart Circ Physiol 301:H115–H122

    Article  PubMed  CAS  Google Scholar 

  • Gabel SA, Walker VR, London RE, Steenbergen C, Korach KS, Murphy E (2005) Estrogen receptor beta mediates gender differences in ischemia/reperfusion injury. J Mol Cell Cardiol 38:289–297

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Segura LM, Sanz A, Mendez P (2006) Cross-talk between IGF-I and estradiol in the brain: focus on neuroprotection. Neuroendocrinology 84:275–279

    Article  PubMed  CAS  Google Scholar 

  • Gardner JD, Brower GL, Janicki JS (2002) Gender differences in cardiac remodeling secondary to chronic volume overload. J Card Fail 8:101–107

    Article  PubMed  Google Scholar 

  • Grohe C, Kahlert S, Lobbert K, Stimpel M, Karas RH, Vetter H, Neyses L (1997) Cardiac myocytes and fibroblasts contain functional estrogen receptors. FEBS Lett 416:107–112

    Article  PubMed  CAS  Google Scholar 

  • Groten T, Pierce AA, Huen AC, Schnaper HW (2005) 17 beta-estradiol transiently disrupts adherens junctions in endothelial cells. FASEB J 19:1368–1370

    PubMed  CAS  Google Scholar 

  • Gurgen D, Hegner B, Kusch A, Catar R, Chaykovska L, Hoff U, Gross V, Slowinski T, da Costa Goncalves AC, Kintscher U, Gustafsson JA, Luft FC, Dragun D (2011) Estrogen receptor-beta signals left ventricular hypertrophy sex differences in normotensive deoxycorticosterone acetate-salt mice. Hypertension 57:648–654

    Article  PubMed  CAS  Google Scholar 

  • Hale SL, Birnbaum Y, Kloner RA (1996) beta-Estradiol, but not alpha-estradiol, reduced myocardial necrosis in rabbits after ischemia and reperfusion. Am Heart J 132:258–262

    Article  PubMed  CAS  Google Scholar 

  • Haq S, Choukroun G, Kang ZB, Ranu H, Matsui T, Rosenzweig A, Molkentin JD, Alessandrini A, Woodgett J, Hajjar R, Michael A, Force T (2000) Glycogen synthase kinase-3beta is a negative regulator of cardiomyocyte hypertrophy. J Cell Biol 151:117–130

    Article  PubMed  CAS  Google Scholar 

  • Hill JA, Olson EN (2008) Cardiac plasticity. N Engl J Med 358:1370–1380

    Article  PubMed  CAS  Google Scholar 

  • Hsieh YC, Choudhry MA, Yu HP, Shimizu T, Yang S, Suzuki T, Chen J, Bland KI, Chaudry IH (2006) Inhibition of cardiac PGC-1alpha expression abolishes ERbeta agonist-mediated cardioprotection following trauma-hemorrhage. FASEB J 20:1109–1117

    Article  PubMed  CAS  Google Scholar 

  • Jain M, Liao R, Podesser BK, Ngoy S, Apstein CS, Eberli FR (2002) Influence of gender on the response to hemodynamic overload after myocardial infarction. Am J Physiol Heart Circ Physiol 283:H2544–H2550

    PubMed  CAS  Google Scholar 

  • Janczewski AM, Kadokami T, Lemster B, Frye CS, McTiernan CF, Feldman AM (2003) Morphological and functional changes in cardiac myocytes isolated from mice overexpressing TNF-alpha. Am J Physiol Heart Circ Physiol 284:H960–H969

    PubMed  CAS  Google Scholar 

  • Jeanes HL, Tabor C, Black D, Ederveen A, Gray GA (2008) Oestrogen-mediated cardioprotection following ischaemia and reperfusion is mimicked by an oestrogen receptor (ER)alpha agonist and unaffected by an ER beta antagonist. J Endocrinol 197:493–501

    Article  PubMed  CAS  Google Scholar 

  • Jiang C, Poole-Wilson PA, Sarrel PM, Mochizuki S, Collins P, MacLeod KT (1992) Effect of 17 beta-oestradiol on contraction, Ca2+ current and intracellular free Ca2+ in guinea-pig isolated cardiac myocytes. Br J Pharmacol 106:739–745

    Article  PubMed  CAS  Google Scholar 

  • Johnson BD, Zheng W, Korach KS, Scheuer T, Catterall WA, Rubanyi GM (1997) Increased expression of the cardiac L-type calcium channel in estrogen receptor-deficient mice. J Gen Physiol 110:135–140

    Article  PubMed  CAS  Google Scholar 

  • Johnson MS, Moore RL, Brown DA (2006) Sex differences in myocardial infarct size are abolished by sarcolemmal KATP channel blockade in rat. Am J Physiol Heart Circ Physiol 290:H2644–H2647

    Article  PubMed  CAS  Google Scholar 

  • Jovanovic S, Jovanovic A, Shen WK, Terzic A (2000) Low concentrations of 17beta-estradiol protect single cardiac cells against metabolic stress-induced Ca2+ loading. J Am Coll Cardiol 36:948–952

    Article  PubMed  CAS  Google Scholar 

  • Kadokami T, McTiernan CF, Kubota T, Frye CS, Feldman AM (2000) Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression. J Clin Invest 106:589–597

    Article  PubMed  CAS  Google Scholar 

  • Karatas A, Hegner B, de Windt LJ, Luft FC, Schubert C, Gross V, Akashi YJ, Gurgen D, Kintscher U, da Costa Goncalves AC, Regitz-Zagrosek V, Dragun D (2008) Deoxycorticosterone acetate-salt mice exhibit blood pressure-independent sexual dimorphism. Hypertension 51:1177–1183

    Article  PubMed  CAS  Google Scholar 

  • Kim J, Wende AR, Sena S, Theobald HA, Soto J, Sloan C, Wayment BE, Litwin SE, Holzenberger M, LeRoith D, Abel ED (2008) Insulin-like growth factor I receptor signaling is required for exercise-induced cardiac hypertrophy. Mol Endocrinol 22:2531–2543

    Article  PubMed  CAS  Google Scholar 

  • Kolodgie FD, Farb A, Litovsky SH, Narula J, Jeffers LA, Lee SJ, Virmani R (1997) Myocardial protection of contractile function after global ischemia by physiologic estrogen replacement in the ovariectomized rat. J Mol Cell Cardiol 29:2403–2414

    Article  PubMed  CAS  Google Scholar 

  • Konhilas JP, Maass AH, Luckey SW, Stauffer BL, Olson EN, Leinwand LA (2004) Sex modifies exercise and cardiac adaptation in mice. Am J Physiol Heart Circ Physiol 287:H2768–H2776

    Article  PubMed  CAS  Google Scholar 

  • Lee TM, Su SF, Tsai CC, Lee YT, Tsai CH (2000) Cardioprotective effects of 17 beta-estradiol produced by activation of mitochondrial ATP-sensitive K(+)Channels in canine hearts. J Mol Cell Cardiol 32:1147–1158

    Article  PubMed  CAS  Google Scholar 

  • Lee TM, Lin MS, Chou TF, Tsai CH, Chang NC (2004) Adjunctive 17beta-estradiol administration reduces infarct size by altered expression of canine myocardial connexin43 protein. Cardiovasc Res 63:109–117

    Article  PubMed  CAS  Google Scholar 

  • Leinwand LA (2003) Sex is a potent modifier of the cardiovascular system. J Clin Invest 112:302–307

    PubMed  CAS  Google Scholar 

  • Lin J, Steenbergen C, Murphy E, Sun J (2009) Estrogen receptor-beta activation results in S-nitrosylation of proteins involved in cardioprotection. Circulation 120:245–254

    Article  PubMed  CAS  Google Scholar 

  • Liu ML, Xu X, Rang WQ, Li YJ, Song HP (2004) Influence of ovariectomy and 17beta-estradiol treatment on insulin sensitivity, lipid metabolism and post-ischemic cardiac function. Int J Cardiol 97:485–493

    Article  PubMed  Google Scholar 

  • Luczak ED, Leinwand LA (2009) Sex-based cardiac physiology. Annu Rev Physiol 71:1–18

    Article  PubMed  CAS  Google Scholar 

  • Luo J, McMullen JR, Sobkiw CL, Zhang L, Dorfman AL, Sherwood MC, Logsdon MN, Horner JW, DePinho RA, Izumo S, Cantley LC (2005) Class IA phosphoinositide 3-kinase regulates heart size and physiological cardiac hypertrophy. Mol Cell Biol 25:9491–9502

    Article  PubMed  CAS  Google Scholar 

  • Mahmoodzadeh S, Dworatzek E, Fritschka S, Pham TH, Regitz-Zagrosek V (2010) 17beta-Estradiol inhibits matrix metalloproteinase-2 transcription via MAP kinase in fibroblasts. Cardiovasc Res 85:719–728

    Article  PubMed  CAS  Google Scholar 

  • McMullen JR, Shioi T, Huang WY, Zhang L, Tarnavski O, Bisping E, Schinke M, Kong S, Sherwood MC, Brown J, Riggi L, Kang PM, Izumo S (2004) The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase(p110alpha) pathway. J Biol Chem 279:4782–4793

    Article  PubMed  CAS  Google Scholar 

  • McMullen JR, Amirahmadi F, Woodcock EA, Schinke-Braun M, Bouwman RD, Hewitt KA, Mollica JP, Zhang L, Zhang Y, Shioi T, Buerger A, Izumo S, Jay PY, Jennings GL (2007) Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy. Proc Natl Acad Sci U S A 104:612–617

    Article  PubMed  CAS  Google Scholar 

  • Mehilli J, Ndrepepa G, Kastrati A, Nekolla SG, Markwardt C, Bollwein H, Pache J, Martinoff S, Dirschinger J, Schwaiger M, Schomig A (2005) Gender and myocardial salvage after reperfusion treatment in acute myocardial infarction. J Am Coll Cardiol 45:828–831

    Article  PubMed  Google Scholar 

  • Mende S, Bleichner F, Stoeter P, Meuret G (1983) Successful treatment of brain metastases in breast cancer with blood-brain barrier-impervious cytostatics and hormones. Onkologie 6:58–61

    Article  PubMed  CAS  Google Scholar 

  • Mendelsohn ME (2002) Genomic and nongenomic effects of estrogen in the vasculature. Am J Cardiol 90:3F–6F

    Article  PubMed  CAS  Google Scholar 

  • Mendelsohn ME, Karas RH (2005) Molecular and cellular basis of cardiovascular gender differences. Science 308:1583–1587

    Article  PubMed  CAS  Google Scholar 

  • Mendez P, Azcoitia I, Garcia-Segura LM (2003) Estrogen receptor alpha forms estrogen-dependent multimolecular complexes with insulin-like growth factor receptor and phosphatidylinositol 3-kinase in the adult rat brain. Brain Res Mol Brain Res 112:170–176

    Article  PubMed  CAS  Google Scholar 

  • Mendez P, Wandosell F, Garcia-Segura LM (2006) Cross-talk between estrogen receptors and insulin-like growth factor-I receptor in the brain: cellular and molecular mechanisms. Front Neuroendocrinol 27:391–403

    Article  PubMed  CAS  Google Scholar 

  • Mole PA (1978) Increased contractile potential of papillary muscles from exercise-trained rat hearts. Am J Physiol 234:H421–H425

    PubMed  CAS  Google Scholar 

  • Murphy E, Steenbergen C (2007) Gender-based differences in mechanisms of protection in myocardial ischemia-reperfusion injury. Cardiovasc Res 75:478–486

    Article  PubMed  CAS  Google Scholar 

  • Nikolic I, Liu D, Bell JA, Collins J, Steenbergen C, Murphy E (2007) Treatment with an estrogen receptor-beta-selective agonist is cardioprotective. J Mol Cell Cardiol 42:769–780

    Article  PubMed  CAS  Google Scholar 

  • Node K, Kitakaze M, Kosaka H, Minamino T, Funaya H, Hori M (1997) Amelioration of ischemia- and reperfusion-induced myocardial injury by 17beta-estradiol: role of nitric oxide and calcium-activated potassium channels. Circulation 96:1953–1963

    Article  PubMed  CAS  Google Scholar 

  • Nordmeyer J, Eder S, Mahmoodzadeh S, Martus P, Fielitz J, Bass J, Bethke N, Zurbrugg HR, Pregla R, Hetzer R, Regitz-Zagrosek V (2004) Upregulation of myocardial estrogen receptors in human aortic stenosis. Circulation 110:3270–3275

    Article  PubMed  CAS  Google Scholar 

  • Novotny JL, Simpson AM, Tomicek NJ, Lancaster TS, Korzick DH (2009) Rapid estrogen receptor-alpha activation improves ischemic tolerance in aged female rats through a novel protein kinase C epsilon-dependent mechanism. Endocrinology 150:889–896

    Article  PubMed  CAS  Google Scholar 

  • Nuedling S, Kahlert S, Loebbert K, Doevendans PA, Meyer R, Vetter H, Grohe C (1999) 17 Beta-estradiol stimulates expression of endothelial and inducible NO synthase in rat myocardium in-vitro and in-vivo. Cardiovasc Res 43:666–674

    Article  PubMed  CAS  Google Scholar 

  • Oertelt-Prigione S, Regitz-Zagrosek V (2012) Sex and gender aspects in clinical medicine. Springer Science + Business Media, Springer London, Medicine and Public Health, Internal Medicine edn (Berlin: Sabine Oertelt-Prigione, Vera Regitz-Zagrosek)

    Google Scholar 

  • Patten RD, Pourati I, Aronovitz MJ, Baur J, Celestin F, Chen X, Michael A, Haq S, Nuedling S, Grohe C, Force T, Mendelsohn ME, Karas RH (2004) 17beta-estradiol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of phospho-inositide-3 kinase/Akt signaling. Circ Res 95:692–699

    Article  PubMed  CAS  Google Scholar 

  • Patten RD, Pourati I, Aronovitz MJ, Alsheikh-Ali A, Eder S, Force T, Mendelsohn ME, Karas RH (2008) 17 Beta-estradiol differentially affects left ventricular and cardiomyocyte hypertrophy following myocardial infarction and pressure overload. J Card Fail 14:245–253

    Article  PubMed  CAS  Google Scholar 

  • Pedram A, Razandi M, Lubahn D, Liu J, Vannan M, Levin ER (2008) Estrogen inhibits cardiac hypertrophy: role of estrogen receptor-beta to inhibit calcineurin. Endocrinology 149:3361–3369

    Article  PubMed  CAS  Google Scholar 

  • Pelzer T, Jazbutyte V, Hu K, Segerer S, Nahrendorf M, Nordbeck P, Bonz AW, Muck J, Fritzemeier KH, Hegele-Hartung C, Ertl G, Neyses L (2005a) The estrogen receptor-alpha agonist 16alpha-LE2 inhibits cardiac hypertrophy and improves hemodynamic function in estrogen-deficient spontaneously hypertensive rats. Cardiovasc Res 67:604–612

    Article  PubMed  CAS  Google Scholar 

  • Pelzer T, Loza PA, Hu K, Bayer B, Dienesch C, Calvillo L, Couse JF, Korach KS, Neyses L, Ertl G (2005b) Increased mortality and aggravation of heart failure in estrogen receptor-beta knockout mice after myocardial infarction. Circulation 111:1492–1498

    Article  PubMed  CAS  Google Scholar 

  • Petrov G, Regitz-Zagrosek V, Lehmkuhl E, Krabatsch T, Dunkel A, Dandel M, Dworatzek E, Mahmoodzadeh S, Schubert C, Becher E, Hampl H, Hetzer R (2010) Regression of myocardial hypertrophy after aortic valve replacement: faster in women? Circulation 122:S23–S28

    Article  PubMed  Google Scholar 

  • Pfeffer JM, Pfeffer MA, Fletcher P, Fishbein MC, Braunwald E (1982) Favorable effects of therapy on cardiac performance in spontaneously hypertensive rats. Am J Physiol 242:H776–H784

    PubMed  CAS  Google Scholar 

  • Ranki HJ, Budas GR, Crawford RM, Jovanovic A (2001) Gender-specific difference in cardiac ATP-sensitive K(+) channels. J Am Coll Cardiol 38:906–915

    Article  PubMed  CAS  Google Scholar 

  • Ranki HJ, Budas GR, Crawford RM, Davies AM, Jovanovic A (2002) 17Beta-estradiol regulates expression of K(ATP) channels in heart-derived H9c2 cells. J Am Coll Cardiol 40:367–374

    Article  PubMed  CAS  Google Scholar 

  • Schaible TF, Scheuer J (1979) Effects of physical training by running or swimming on ventricular performance of rat hearts. J Appl Physiol 46:854–860

    PubMed  CAS  Google Scholar 

  • Schaible TF, Scheuer J (1981) Cardiac function in hypertrophied hearts from chronically exercised female rats. J Appl Physiol 50:1140–1145

    PubMed  CAS  Google Scholar 

  • Schaible TF, Penpargkul S, Scheuer J (1981) Cardiac responses to exercise training in male and female rats. J Appl Physiol 50:112–117

    PubMed  CAS  Google Scholar 

  • Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK (2000) Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407:538–541

    Article  PubMed  CAS  Google Scholar 

  • Simoncini T, Mannella P, Genazzani AR (2006) Rapid estrogen actions in the cardiovascular system. Ann N Y Acad Sci 1089:424–430

    Article  PubMed  CAS  Google Scholar 

  • Skavdahl M, Steenbergen C, Clark J, Myers P, Demianenko T, Mao L, Rockman HA, Korach KS, Murphy E (2005) Estrogen receptor-beta mediates male-female differences in the development of pressure overload hypertrophy. Am J Physiol Heart Circ Physiol 288:H469–H476

    Article  PubMed  CAS  Google Scholar 

  • Sun J, Picht E, Ginsburg KS, Bers DM, Steenbergen C, Murphy E (2006) Hypercontractile female hearts exhibit increased S-nitrosylation of the L-type Ca2+ channel alpha1 subunit and reduced ischemia/reperfusion injury. Circ Res 98:403–411

    Article  PubMed  CAS  Google Scholar 

  • van Eickels M, Grohe C, Cleutjens JP, Janssen BJ, Wellens HJ, Doevendans PA (2001) 17beta-estradiol attenuates the development of pressure-overload hypertrophy. Circulation 104:1419–1423

    Article  PubMed  Google Scholar 

  • Varea O, Arevalo MA, Garrido JJ, Garcia-Segura LM, Wandosell F, Mendez P (2010) Interaction of estrogen receptors with insulin-like growth factor-I and Wnt signaling in the nervous system. Steroids 75:565–569

    Article  PubMed  CAS  Google Scholar 

  • Vornehm ND, Wang M, Abarbanell A, Herrmann J, Weil B, Tan J, Wang Y, Kelly M, Meldrum DR (2009) Acute postischemic treatment with estrogen receptor-alpha agonist or estrogen receptor-beta agonist improves myocardial recovery. Surgery 146:145–154

    Article  PubMed  Google Scholar 

  • Wang M, Baker L, Tsai BM, Meldrum KK, Meldrum DR (2005) Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury. Am J Physiol Endocrinol Metab 288:E321–E326

    Article  PubMed  CAS  Google Scholar 

  • Wang C, Chiari PC, Weihrauch D, Krolikowski JG, Warltier DC, Kersten JR, Pratt PF Jr, Pagel PS (2006a) Gender-specificity of delayed preconditioning by isoflurane in rabbits: potential role of endothelial nitric oxide synthase. Anesth Analg 103:274–280, table of contents

    Article  PubMed  CAS  Google Scholar 

  • Wang M, Crisostomo P, Wairiuko GM, Meldrum DR (2006b) Estrogen receptor-alpha mediates acute myocardial protection in females. Am J Physiol Heart Circ Physiol 290:H2204–H2209

    Article  PubMed  CAS  Google Scholar 

  • Wang M, Tsai BM, Reiger KM, Brown JW, Meldrum DR (2006c) 17-beta-Estradiol decreases p38 MAPK-mediated myocardial inflammation and dysfunction following acute ischemia. J Mol Cell Cardiol 40:205–212

    Article  PubMed  CAS  Google Scholar 

  • Wang M, Wang Y, Weil B, Abarbanell A, Herrmann J, Tan J, Kelly M, Meldrum DR (2009) Estrogen receptor beta mediates increased activation of PI3K/Akt signaling and improved myocardial function in female hearts following acute ischemia. Am J Physiol Regul Integr Comp Physiol 296:R972–R978

    Article  PubMed  CAS  Google Scholar 

  • Weinberg EO, Thienelt CD, Katz SE, Bartunek J, Tajima M, Rohrbach S, Douglas PS, Lorell BH (1999) Gender differences in molecular remodeling in pressure overload hypertrophy. J Am Coll Cardiol 34:264–273

    Article  PubMed  CAS  Google Scholar 

  • Weinberg EO, Mirotsou M, Gannon J, Dzau VJ, Lee RT, Pratt RE (2003) Sex dependence and temporal dependence of the left ventricular genomic response to pressure overload. Physiol Genomics 12:113–127

    PubMed  CAS  Google Scholar 

  • Witt H, Schubert C, Jaekel J, Fliegner D, Penkalla A, Tiemann K, Stypmann J, Roepcke S, Brokat S, Mahmoodzadeh S, Brozova E, Davidson MM, Ruiz Noppinger P, Grohe C, Regitz-Zagrosek V (2008) Sex-specific pathways in early cardiac response to pressure overload in mice. J Mol Med (Berl) 86:1013–1024

    Article  Google Scholar 

  • Xin HB, Senbonmatsu T, Cheng DS, Wang YX, Copello JA, Ji GJ, Collier ML, Deng KY, Jeyakumar LH, Magnuson MA, Inagami T, Kotlikoff MI, Fleischer S (2002) Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy. Nature 416:334–338

    Article  PubMed  CAS  Google Scholar 

  • Xu Y, Arenas IA, Armstrong SJ, Davidge ST (2003) Estrogen modulation of left ventricular remodeling in the aged heart. Cardiovasc Res 57:388–394

    Article  PubMed  CAS  Google Scholar 

  • Xu Y, Arenas IA, Armstrong SJ, Plahta WC, Xu H, Davidge ST (2006) Estrogen improves cardiac recovery after ischemia/reperfusion by decreasing tumor necrosis factor-alpha. Cardiovasc Res 69:836–844

    Article  PubMed  CAS  Google Scholar 

  • Yu HP, Shimizu T, Choudhry MA, Hsieh YC, Suzuki T, Bland KI, Chaudry IH (2006) Mechanism of cardioprotection following trauma-hemorrhagic shock by a selective estrogen receptor-beta agonist: up-regulation of cardiac heat shock factor-1 and heat shock proteins. J Mol Cell Cardiol 40:185–194

    Article  PubMed  CAS  Google Scholar 

  • Zhai P, Eurell TE, Cooke PS, Lubahn DB, Gross DR (2000) Myocardial ischemia-reperfusion injury in estrogen receptor-alpha knockout and wild-type mice. Am J Physiol Heart Circ Physiol 278:H1640–H1647

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S. Mahmoodzadeh .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Mahmoodzadeh, S., Fliegner, D., Dworatzek, E. (2013). Sex Differences in Animal Models for Cardiovascular Diseases and the Role of Estrogen. In: Regitz-Zagrosek, V. (eds) Sex and Gender Differences in Pharmacology. Handbook of Experimental Pharmacology, vol 214. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-30726-3_2

Download citation

Publish with us

Policies and ethics