Cardiac remodeling is regulated by c-Myc : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
| Published: |
[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2012]
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| Subjects: |
| Abstract: | ABSTRACT: Objective: In response to pathological stimuli, cardiac remodeling ensues in an attempt to compensate for the increased load. Processes including cardiomyocyte hypertrophy, ECM deposition, angiogenesis and metabolic shifts are initially cardioprotective and maintain cardiac output; however, chronically these remodeling events contribute to decompensation and eventual heart failure. While current treatments focus mainly on blocking the remodeling stimulus, effective future treatments will address downstream pathways to prevent the pathological remodeling. One such target is the transcription factor, c-Myc, which has a profound effect on cardiac hypertrophy and has been shown to regulate angiogenesis and metabolism in malignancies. We hypothesize that c-Myc guides processes regulating both compensated and decompensated cardiac remodeling and could be targeted in the future to attenuate cardiac dysfunction. Methods and Results: Using the transverse aortic constriction mouse model to induce pressure overload stress on the heart, here we describe critical early and late remodeling events, including myocyte hypertrophy, fibrosis, vascular remodeling and changes in cardiac cell populations. The role of c-Myc in each of these processes was determined using c-myc knockout mouse models and Myc expression in endothelial cells, fibroblasts and myocytes is critical to formation and remodeling of the coronary vasculature via secreted pro-angiogenic factors as well as direct cell-cell interactions. In addition, cardiomyocyte-specific c-Myc expression is required early in response to pressure overload to avoid cardiac dysfunction, which is associated with cardiomyocyte apoptosis and an inability to properly regulate metabolism in response to stress. Conversely, cardiomyocyte Myc knockout after these initial remodeling events occur is cardioprotective and prevents systolic cardiac dysfunction and excessive fibrosis. Conclusions: The multitude of processes regulated by c-Myc designates it as an essential stress-response factor to mediate compensated cardiac hypertrophy. Interestingly, its chronic expression also contributes to decompensation to heart failure by promoting pathological remodeling (aside from enhancing angiogenesis). These properties make c-Myc inhibition an intriguing target as a broad treatment for heart disease and prevention of pathological remodeling. |
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| Item Description: | Vita. "Major Subject: Biomedical Sciences". "Submitted to the Office of Research and Graduate Studies of The Texas A&M University System Health Science Center in partial fulfillment of the requirements for the degree of Doctorate of Philosophy May 19th 2012." Approved as to style and content by: Troy A. Baudino, Brett M. Mitchell, David E. Dostal, Alejandro C. Arroliga, Shaodong Guo |
| Physical Description: | xii, 152 leaves : illustrations (mostly color) ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 129-150). |