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Delineating the Role of c-Myc in Development and Propagation of Hypertrophic Cardiomyopathy

Wolfram, Julie Ann
http://rave.ohiolink.edu/etdc/view?acc_num=case1315603810

Abstract Details

2012, Doctor of Philosophy, Case Western Reserve University, Pathology.
Cardiovascular disease continues to be the leading cause of morbidity and mortality in the world. Among cardiovascular diseases in general, heart failure is the fastest growing subclass over the last 20 years. Heart failure is typically induced by a number of stimuli including congenital cardiovascular malformations, valvular insufficiency and stenosis, hypertension and mutations inducing hypertrophy and contractility dysfunction. In particular, hypertrophy, characterized by an increase of individual cell size of cardiomyocytes and reactivation of cardiac fetal genes, initially acts as an adaptive response to various stimuli physiologically. However, when hypertrophy becomes pathological due to prolonged stimulation, it can cause cardiac dysfunction and insufficiency and sudden death. Hypertrophic cardiomyopathy (HCM), a disease of the heart muscle, is typically characterized by mutations in contractile proteins of the sarcomere, leading to deterioration of function and eventually heart failure. In addition to known familial mutations, the proto-oncogene c-Myc (Myc) has been shown to be increased in hearts with HCM. Myc also is known to be important in heart development and cardiomyocyte proliferation. Following development, levels of Myc are decreased leading to cell cycle arrest in cardiomyocytes. However, in patients with HCM, Myc is re-expressed and cell cycle changes occur. This pathological dysfunction and increase in Myc is part of the fetal re-expression program and is poorly understood. To investigate the role of Myc in HCM and hypertrophy, we have developed a bitransgenic mouse that inducibly overexpresses Myc under the control of the cardiomyocyte specific myosin heavy chain promoter. Adult mice overexpressing Myc in the cardiomyocytes develop severe HCM characterized by hypertrophy, ventricular dysfunction and ultimately heart failure. Induction of Myc results in cell cycle re-entry, accumulation of DNA damage, mitochondria dysfunction, increases in apoptosis and alterations in connexin 43 expression and localization. This phenotype can be decreased and delayed by reducing the amount of Myc gene expression induced in the Myc-On mouse. Additionally, the hypertrophy is reversible when Myc is turned off after 10 days of gene induction, but is irreversible after 2 weeks of Myc gene induction. Animals with Myc turned off after 2 weeks still develop heart failure and die. Using this cardiomyocyte specific, Myc overexpressing mouse model, we investigated the role of Myc in hypertrophy, cell cycle re-entry, DNA damage accumulation, increased apoptosis and alterations in connexin 43 expression. We also used this model to test various hypertrophic reducing compounds including Curcumin, tamoxifen and blueberries. This is a unique model to study hypertrophic reducing and cardioprotective molecules as we can modulate the duration and severity of disease by varying the levels of Myc. Taken together, our findings suggest that Myc induction leads to a specific series of events responsible for the development and propagation of HCM and that these alterations to the cellular makeup of cardiomyocytes leads to destabilization of the myocardium and ultimately heart failure.
Hyoung-gon Lee, PhD (Advisor)
Nicholas Ziats, PhD (Committee Chair)
Steven Emancipator, MD (Committee Member)
Brian Hoit, MD (Committee Member)
Clive Hamlin, PhD (Committee Member)
149 p.
Cellular Biology; Medicine; Molecular Biology
hypertrophic cardiomyopathy; c-Myc; cell cycle; transgenic mouse model

Recommended Citations

Citations

  • Wolfram, J. A. (2012). Delineating the Role of c-Myc in Development and Propagation of Hypertrophic Cardiomyopathy [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1315603810

    APA Style (7th edition)

  • Wolfram, Julie. Delineating the Role of c-Myc in Development and Propagation of Hypertrophic Cardiomyopathy. 2012. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1315603810.

    MLA Style (8th edition)

  • Wolfram, Julie. "Delineating the Role of c-Myc in Development and Propagation of Hypertrophic Cardiomyopathy." Doctoral dissertation, Case Western Reserve University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1315603810

    Chicago Manual of Style (17th edition)

case1315603810
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© 2011, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.