Sex-specific modulators of mitochondrial function
Final Report Abstract
Several studies indicated that sex, sex hormones, particularly 17ß-estradiol (E2) and the estrogen receptors (ER) influence the development of physiological and pathological myocardial hypertrophy (MH), fibrosis and heart failure. However, the underlying molecular mechanisms are not understood in detail. Therefore, we analyzed the role of sex and E2/ER in the myocardial adaptation process in male and female WT, ERα- (ERKO) and ERβ-knockout (BERKO) mice in response to voluntary cage wheel running (VCR). We showed that VCR-induced physiological MH is more pronounced in female WT compared with male WT mice. This was associated with the greater activation of AKT, p38- and ERK1/2-MAPK, protein synthesis and mitochondrial adaptation in females. Using BERKO mice, we could show that ERβ modulates the development of physiological MH in both sexes. Since ERKO mice did not run in a similar manner as WT and BERKO mice, they were not considered as an appropriate model to analyze the effects of ERα on physiological MH. Mechanistic studies in AC16 cells support the role of E2/ER on modulation of mitochondrial regulatory genes. In particular, E2 via ERβ enhances the expression of MEF2A, NRF1, NRF2A/B, and Tfam. Further, we showed that E2 induces the nuclear translocation of MEF2a in cardiomyocytes. To exclude systemic effects of ER, we generated novel mouse models with a cardiomyocyte-specific deletion of ERα (CM-ERαKO) or ERβ (CM-ERβKO). Using CM-ERβKO, we confirmed that ERβ specifically in cardiomyocytes is pivotal for induction of physiological MH in both sexes. CM-ERαKO mice are still under investigation, due to delivery difficulties of flox-ERα mice. Additionally, we generated mice with a cardiomyocyte specific 16 ERα- or ERβ-overexpression, and subjected them to myocardial infarction. Thereby, we could show that development of pathological MH and cardiac remodeling is affected by ERα and ERβ in a sex- dependent manner and identified the underlyingmechanisms.
Publications
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Nuclear factor-kappaB regulates estrogen receptor-alpha transcription in the human heart. J Biol Chem. 2009;284(37):24705-14
Mahmoodzadeh S, Fritschka S, Dworatzek E, Pham TH, Becher E, Kuehne A, Davidson MM, Regitz-Zagrosek V
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beta-Estradiol inhibits matrix metalloproteinase-2 transcription via MAP kinase in fibroblasts. Cardiovasc Res. 2010;85(4):719-28.17
Mahmoodzadeh S, Dworatzek E, Fritschka S, Pham TH, Regitz-Zagrosek V
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Regression of myocardial hypertrophy after aortic valve replacement: faster in women? Petrov G, Circulation. 2010;122(11 Suppl):S23-8
Regitz-Zagrosek V, Lehmkuhl E, Krabatsch T, Dunkel A, Dandel M, Dworatzek E, Mahmoodzadeh S, Schubert C, Becher E, Hampl H, Hetzer R
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Role of the estrogen/estrogenreceptor-beta axis in the genomic response to pressure overload-induced hypertrophy. Physiol Genomics. 2011;43(8):438-46
Kararigas G, Fliegner D, Gustafsson JÅ, Regitz-Zagrosek V
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Sex differences in physiological cardiac hypertrophy are associated with exercise-mediated changes in energy substrate availability. Am J Physiol Heart Circ Physiol. 2011;301(1):H115-22
Foryst-Ludwig A, Kreissl MC, Sprang C, Thalke B, Böhm C, Benz V, Gürgen D, Dragun D, Schubert C, Mai K, Stawowy P, Spranger J, Regitz-Zagrosek V, Unger T, Kintscher U
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17β-Estradiol-induced interaction of ERα with NPPA regulates gene expression in cardiomyocytes. Cardiovasc Res. 2012;96(3):411-21
Mahmoodzadeh S, Pham TH, Kuehne A, Fielitz B, Dworatzek E, Kararigas G, Petrov G, Davidson MM, Regitz-Zagrosek V
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Effects of estrogen, an ERα agonist and raloxifene on pressure overload induced cardiac hypertrophy. PLoS One. 2012;7(12)
Westphal C, Schubert C, Prelle K, Penkalla A, Fliegner D, Petrov G, Regitz-Zagrosek V
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Gender-specific predictors of early mortality after coronary artery bypass graft surgery. Clin Res Cardiol. 2012;101(9):745-51
Lehmkuhl E, Kendel F, Gelbrich G, Dunkel A, Oertelt-Prigione S, Babitsch B, Knosalla C, Bairey- Merz N, Hetzer R, Regitz-Zagrosek V
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CYP2J2 overexpression protects against arrhythmia susceptibility in cardiac hypertrophy. PLoS One. 2013;8(8)
Westphal C, Spallek B, Konkel A, Marko L, Qadri F, DeGraff LM, Schubert C, Bradbury JA, Regitz- Zagrosek V, Falck JR, Zeldin DC, Müller DN, Schunck WH, Fischer R
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Sex and sex hormone-dependent cardiovascular stress responses. Hypertension. 2013;61(2):270-7
Regitz-Zagrosek V, Dworatzek E, Kintscher U, Dragun D
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Sex- and estrogen-dependent regulation of a miRNA network in the healthy and hypertrophied heart. Int J Cardiol. 2013;169(5):331-8
Queirós AM, Eschen C, Fliegner D, Kararigas G, Dworatzek E, Westphal C, Sanchez Ruderisch H, Regitz-Zagrosek V
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Cardiomyocyte-specific Estrogen Receptor Alpha Increases Angiogenesis, Lymphangiogenesis and Reduces Fibrosis in the Female Mouse Heart Post-Myocardial Infarction. J Cell Sci Ther. 2014;5(1):153
Mahmoodzadeh S, Leber J, Zhang X, Jaisser F, Messaoudi S, Morano I, Furth PA, Dworatzek E, Regitz-Zagrosek V
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Maladaptive Remodeling Is AssociatedWith Impaired Survival in Women but Not in Men After Aortic Valve Replacement.JACC Cardiovasc Imaging. JACC Cardiovasc Imaging. 2014;7(11)
Petrov G, Dworatzek E, Schulze TM, Dandel M, Kararigas G, Mahmoodzadeh S, Knosalla C, Hetzer R, Regitz-Zagrosek V
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Sex differences in exercise-induced physiological myocardial hypertrophy are modulated by oestrogen receptor beta. Cardiovasc Res. 2014;102(3):418-28
Dworatzek E, Mahmoodzadeh S, Schubert C, Westphal C, Leber J, Kusch A, Kararigas G, Fliegner D, Moulin M, Ventura-Clapier R, Gustafsson JA, Davidson MM, Dragun D, Regitz-Zagrosek V
