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    The Role of Calcium in the Regulation of Pathological Hypertrophy

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    Genre
    Thesis/Dissertation
    Date
    2014
    Author
    Barr, Larry A.
    Advisor
    Houser, Steven R.
    Committee member
    Rizzo, Victor
    Chen, Xiongwen
    Libonati, Joseph R.
    Rabinowitz, Peter J., 1944-
    Department
    Physiology
    Subject
    Physiology
    Biology, Molecular
    Pharmacology
    Calcium
    Cardiomyopathy
    Exercise
    Heart Failure
    Hypertrophy
    Imatinib
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/2583
    
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    DOI
    http://dx.doi.org/10.34944/dspace/2565
    Abstract
    Pathological hypertrophy leads to cardiac dysfunction and heart failure. It is not clearly defined how this process occurs in the cardiomyocyte, or how the pathology can be effectively treated. There are numerous processes that lead to pathological hypertrophy. We developed two models to study pathological hypertrophy and the role that Ca2+ plays. In one model, we administered clinical doses of the leukemia therapeutic drug imatinib to neonatal ventricular cardiomyocytes. This drug has recently been found to be cardiotoxic, and we set out to understand if Ca2+ is involved. In the second model, we developed mice with overexpression of the Ca2+ entrance channel, the L-type calcium channel (LTCC), which leads to pathological hypertrophy over time. We instituted a chronic exercise regimen on these mice to learn if physiological hypertrophy can ameliorate detrimental aspects of pathological hypertrophy. After cardiomyocytes were treated with imatinib, they expressed enhanced Ca2+ activity. Levels of atrial natriuretic peptide (ANP) were up, signifying pathological hypertrophy. We determined that Ca2+ was activating Calcineurin, leading to translocation of nuclear factor of activated T-cells (NFAT) into the nucleus, resulting in hypertrophy. This activity was blocked by Ca2+ and Calcineurin inhibitors. We concluded that imatinib causes Ca2+ induced pathological hypertrophy. When mice with LTCC overexpression were exercised, they exhibited enhanced cardiac function. They also had thicker septal walls and increased chamber diameter, hallmarks of physiological hypertrophy. Heart weight to body weight ratio was significantly higher after exercise. When isolated hearts were administered ischemia/reperfusion injury, the exercised hearts showed a significant improvement in recovery compared to sedentary LTCC overexpressed hearts. Calcium activity was enhanced at the cardiomyocyte level in both mouse lines of exercised mice. In conclusion, hearts with a pathological hypertrophic phenotype can enhance function and achieve cardioprotection through chronic exercise.
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