Estrogenic compounds are not always cardioprotective and can be lethal in males with genetic heart disease

Christopher D. Haines, Pamela A. Harvey, Elizabeth D. Luczak, Kristen K B Barthel, John Konhilas, Peter A. Watson, Brian L. Stauffer, Leslie A. Leinwand

Research output: Contribution to journalArticle

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Abstract

Hypertrophic cardiomyopathy (HCM) is more severe in male than female mice eating a soy-based diet. We sought to determine whether the detrimental effects are mediated by the phytoestrogens present in soy, the mechanism by which phytoestrogens act, and to test whether estrogen modulates the sexually dimorphic phenotype. A soy-free diet (casein based) supplemented with the predominant phytoestrogens in soy, genistein and daidzein, recapitulated the fibrotic, proapoptotic and negative hemodynamic effects of soy in male hearts. As with the soy diet, the hearts of female HCM mice were not negatively affected by the phytoestrogen-containing diet. To determine the role of estrogen in the sex differences mediated by diet in HCM, gonadectomies were performed and estrogen was administered to male and female HCM mice on a casein- or phytoestrogen-supplemented diet. Somewhat surprisingly, estrogen was not protective in male or female mice with HCM and, in fact, was lethal in phytoestrogen-fed male mice with HCM. Because genistein is a potent tyrosine kinase inhibitor and tyrosine kinase inhibition has been associated with cardiotoxicity, we tested its effects in isolated adult cardiac myocytes. Genistein inhibited different tyrosine kinases depending on sex and, in combination with estrogen, resulted in apoptosis only in adult male cardiac myocytes. Finally, we show that phytoestrogens led to distinct programs of gene expression in hearts from males vs. females with HCM, suggesting mechanisms by which males are more sensitive to the detrimental effects of phytoestrogens and females are protected. These results implicate the phytoestrogen genistein in mediating cardiac pathology in males with HCM and, importantly, establish that estrogen is not protective in the setting of HCM.

Original languageEnglish (US)
Pages (from-to)4470-4479
Number of pages10
JournalEndocrinology
Volume153
Issue number9
DOIs
StatePublished - Sep 1 2012

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Phytoestrogens
Inborn Genetic Diseases
Hypertrophic Cardiomyopathy
Heart Diseases
Estrogens
Genistein
Diet
Protein-Tyrosine Kinases
Caseins
Cardiac Myocytes
Sex Characteristics
Eating
Hemodynamics
Apoptosis
Pathology
Phenotype
Gene Expression

ASJC Scopus subject areas

  • Endocrinology

Cite this

Haines, C. D., Harvey, P. A., Luczak, E. D., Barthel, K. K. B., Konhilas, J., Watson, P. A., ... Leinwand, L. A. (2012). Estrogenic compounds are not always cardioprotective and can be lethal in males with genetic heart disease. Endocrinology, 153(9), 4470-4479. https://doi.org/10.1210/en.2012-1391

Estrogenic compounds are not always cardioprotective and can be lethal in males with genetic heart disease. / Haines, Christopher D.; Harvey, Pamela A.; Luczak, Elizabeth D.; Barthel, Kristen K B; Konhilas, John; Watson, Peter A.; Stauffer, Brian L.; Leinwand, Leslie A.

In: Endocrinology, Vol. 153, No. 9, 01.09.2012, p. 4470-4479.

Research output: Contribution to journalArticle

Haines, CD, Harvey, PA, Luczak, ED, Barthel, KKB, Konhilas, J, Watson, PA, Stauffer, BL & Leinwand, LA 2012, 'Estrogenic compounds are not always cardioprotective and can be lethal in males with genetic heart disease', Endocrinology, vol. 153, no. 9, pp. 4470-4479. https://doi.org/10.1210/en.2012-1391
Haines, Christopher D. ; Harvey, Pamela A. ; Luczak, Elizabeth D. ; Barthel, Kristen K B ; Konhilas, John ; Watson, Peter A. ; Stauffer, Brian L. ; Leinwand, Leslie A. / Estrogenic compounds are not always cardioprotective and can be lethal in males with genetic heart disease. In: Endocrinology. 2012 ; Vol. 153, No. 9. pp. 4470-4479.
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