The heart responds to diverse stimuli by morphological and functional adaptation. The cardiac adaptive repertoire is stimulus-specific. For example, endurance exercise yields eccentric hypertrophy, while pressure overload or certain mutant sarcomeric proteins can provoke concentric hypertrophy. We will explore the pathways leading to these physiologic and pathologic adaptations and we will determine the potential roles of diet and sex in modifying them. The diagram at the left illustrates the overall goals of this proposal. We have recently found that substituting a casein-based diet for the traditional soy-based diet in a mouse model of hypertrophic cardiomyopathy (HCM) has profound and unexpected effects on pathogenesis. It therefore seems plausible that phytoestrogens in standard rodent chow dramatically affect disease and may also affect exercise adaptation; what is the mechanism of this effect? Genetic mouse models will be employed to ask the following questions: 1) which known signaling pathways play a role in HCM? 2) what role do those same pathways play in exercise adaptation? 3) how do sex and diet modify these adaptations? Mouse models that can potentially answer such questions are in hand: models of HCM with mutations in myosin heavy chain (MyHC) or cardiac troponin T (cTnT), and mice with alterations in cardiac signaling molecules. Genetic crosses among them will contribute to answering these questions. The signaling molecules and pathways that we have chosen to pursue include: CaMK, Akt, GSK3a, MEKK1, ERK1/2, JNK, p38 and MEF2. In order to extend our studies beyond these selected pathways and molecules, we will also assess global gene expression changes in the heart that occur between the sexes and how dietary and exercise interventions affect them. We feel that these approaches will be very useful to our understanding of the basic biology of adaptive and maladaptive cardiac hypertrophy and pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050560-14
Application #
7073383
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Liang, Isabella Y
Project Start
1993-07-01
Project End
2008-04-14
Budget Start
2006-07-01
Budget End
2008-04-14
Support Year
14
Fiscal Year
2006
Total Cost
$473,736
Indirect Cost
Name
University of Colorado at Boulder
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
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; Harvey, Pamela A; Leinwand, Leslie A (2012) Interferon-? causes cardiac myocyte atrophy via selective degradation of myosin heavy chain in a model of chronic myocarditis. Am J Pathol 181:2038-46
Haines, Christopher D; Harvey, Pamela A; Luczak, Elizabeth D et al. (2012) Estrogenic compounds are not always cardioprotective and can be lethal in males with genetic heart disease. Endocrinology 153:4470-9
Spangenburg, Espen E; Geiger, Paige C; Leinwand, Leslie A et al. (2012) Regulation of physiological and metabolic function of muscle by female sex steroids. Med Sci Sports Exerc 44:1653-62

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