During the last grant period we uncovered a substantial effect of diet on the rodent heart that is gender dimorphic. The standard soy-based rodent diet has a negative impact on males compared to females in both hypertrophic cardiomyopathy and exercise. The detrimental dietary effects of soy on males can be attributed to the phytoestrogens in the soy diet. These phenotypic differences are supported by expression array data which show that more genes are regulated by the soy diet (and by purified phytoestrogens) in male than in female hearts. We wish to understand the molecular mechanisms whereby diet, gender and exercise mediate their effects on the heart and hypothesize that microRNAs regulate these global effects. We will determine the role that estrogen receptor (ER) signaling plays in these phytoestrogen-stimulated events. Given the finding that dietary effects are not restricted to the heart, but are also seen in liver and skeletal muscle, we hypothesize that there is functional interaction among these organs and propose to understand its basis. The proposal has three major Aims. First, the mechanisms whereby diet and gender modify pathologic cardiac adaptation will be determined. Second, the mechanisms of cardiac and skeletal muscle cross-talk in disease will be defined. Third, the critical pathways underlying cardiac adaptation in response to exercise will be identified. We believe that we are in an excellent position to understand the mechanisms of action of these potent modifiers of cardiac adaptation that have not yet been addressed in molecular detail.

Public Health Relevance

Male hearts generally respond less well to heart disease than female hearts and estrogen remains a candidate to explain this gender difference. In addition to consideration of endogenous estrogen, environmental agents like plant estrogens in soy that can affect the actions of endogenous hormones are of increasing concern to the general public. Since the vast majority of laboratory rodents consume a soy- based diet, we question how the soy diet affects the phenotypes of many animals under study in laboratories and also how increasing ingestion of plant estrogens affects human health.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Liang, Isabella Y
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University of Colorado at Boulder
Schools of Arts and Sciences
United States
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Konhilas, John P; Chen, Hao; Luczak, Elizabeth et al. (2015) Diet and sex modify exercise and cardiac adaptation in the mouse. Am J Physiol Heart Circ Physiol 308:H135-45
Harvey, Pamela Ann; Leinwand, Leslie Anne (2015) Dietary phytoestrogens present in soy dramatically increase cardiotoxicity in male mice receiving a chemotherapeutic tyrosine kinase inhibitor. Mol Cell Endocrinol 399:330-5
Harvey, Pamela Ann; Leinwand, Leslie Anne (2015) Oestrogen enhances cardiotoxicity induced by Sunitinib by regulation of drug transport and metabolism. Cardiovasc Res 107:66-77
Chung, Eunhee; Leinwand, Leslie A (2014) Pregnancy as a cardiac stress model. Cardiovasc Res 101:561-70
Magida, Jason A; Leinwand, Leslie A (2014) Metabolic crosstalk between the heart and liver impacts familial hypertrophic cardiomyopathy. EMBO Mol Med 6:482-95
Chung, Eunhee; Yeung, Fan; Leinwand, Leslie A (2013) Calcineurin activity is required for cardiac remodelling in pregnancy. Cardiovasc Res 100:402-10
McKee, Laurel A K; Chen, Hao; Regan, Jessica A et al. (2013) Sexually dimorphic myofilament function and cardiac troponin I phosphospecies distribution in hypertrophic cardiomyopathy mice. Arch Biochem Biophys 535:39-48
Cosper, Pippa F; Leinwand, Leslie A (2012) Myosin heavy chain is not selectively decreased in murine cancer cachexia. Int J Cancer 130:2722-7
Wang, Huan; Haeger, Sarah M; Kloxin, April M et al. (2012) Redirecting valvular myofibroblasts into dormant fibroblasts through light-mediated reduction in substrate modulus. PLoS One 7:e39969
Haines, Christopher D; Harvey, Pamela A; Leinwand, Leslie A (2012) Estrogens mediate cardiac hypertrophy in a stimulus-dependent manner. Endocrinology 153:4480-90

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