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The Role of Tsg101 in the Development of Physiological Cardiac Hypertrophy and Cardio-Protection from Endotoxin-Induced Cardiac Dysfunction

Essandoh, Kobina

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2019, PhD, University of Cincinnati, Medicine: Molecular, Cellular and Biochemical Pharmacology.
In this dissertation, the functional role of Tumor susceptibility gene (Tsg101) in the regulation of physiological cardiac hypertrophy and endotoxin-induced cardiac dysfunction was explored. Development of physiological cardiac hypertrophy has primarily been ascribed to the insulin-like growth factor 1 (IGF-1) and its receptor, IGF-1R, and subsequent activation of the Akt pathway. However, regulation of endosome-mediated recycling and degradation of IGF-1R during physiological hypertrophy has not been investigated. Furthermore, cardiac mitochondrial damage and subsequent inflammation are hallmarks of endotoxin-induced myocardial depression. Activation of the Parkin/PINK1 pathway has been shown to promote autophagy of damaged mitochondria (mitophagy) and protect from endotoxin-induced cardiac dysfunction. Tsg101 has been demonstrated to play diverse roles in the cell including virus budding, cytokinesis, transcriptional regulation, endosomal recycling of receptors and activation of autophagic flux. Hence, the first goal of this dissertation was to elucidate the role of Tg101 in endosome-mediated recycling of IGF-1R in physiological cardiac remodeling. The second goal of this dissertation was to investigate whether Tsg101 regulates mitophagy and thus contribute to endotoxin-caused myocardial dysfunction. Firstly, in a physiological hypertrophy model of treadmill-exercised mice, we observed that levels of Tsg101 were dramatically elevated in the heart, compared to sedentary controls. To determine the role of Tsg101 on physiological hypertrophy, we generated a transgenic mouse model with cardiac-specific overexpression of Tsg101. These transgenic (TG) mice exhibited physiological cardiac hypertrophy at 8 weeks, evidenced by significant enhancement of cardiac function without fibrosis, increased total and membrane levels of IGF-1R, as well as Akt activation, compared to wild-types. Mechanistically, we identified that Tsg101 interacted with FIP3 and IGF-1R, thereby stabilizing the endosomal recycling compartment (ERC) and enhancing recycling of IGF-1R. In vitro, adenovirus-mediated overexpression of Tsg101 in neonatal rat cardiomyocytes resulted in cell hypertrophy, which was blocked by addition of 1) Monensin, an inhibitor of endosomal recycling; 2) Picropodophyllin, an inhibitor of IGF-1R signaling; and 3) siRNA-FIP3. Furthermore, knockdown of Tsg101 in both mice and neonatal cardiomyocytes significantly inhibited the expression of Rab11a and FIP3 and endosomal recycling of IGF-1R, compared to controls. Interestingly, inducible Tsg101-knockdown mice failed to develop cardiac hypertrophy after treadmill training. Additionally, Tsg101-TG were protected from cardiac fibrosis and dysfunction associated with pathological hypertrophy, induced by transverse aortic constriction surgery. Secondly, Tsg101-TG and -KD mice underwent endotoxin (LPS) treatment (10µg/g) to determine survival, cardiac function, systemic/local inflammation, and activity of mitophagy mediators in the heart. Upon endotoxin challenge, Tsg101-TG mice exhibited decreased mortality, preserved cardiac contractile function, reduced inflammation, enhanced activation of mitophagy in the heart and preservation of mitochondrial structural integrity, compared to control mice. By contrast, endoxin treatment in Tsg101-KD mice exacerbated animal mortality, cardiac dysfunction, inflammation and mitochondrial structural damage. Both co-immunoprecipitation assays and co-immunofluorescence staining showed that Tsg101 was bound to Parkin in the cytosol of myocytes and consequently facilitated translocation of Parkin to the mitochondria. Altogether, this dissertation demonstrates that Tsg101: a) regulates physiological cardiac hypertrophy through the FIP3-mediated endosomal recycling of IGF-1R; and b) could protect against endotoxin-triggered myocardial injury by promoting Parkin-induced mitophagy.
Guochang Fan, Ph.D. (Committee Chair)
Charles Caldwell, Ph.D. (Committee Member)
Terence Kirley, Ph.D. (Committee Member)
Evangelia Kranias, Ph.D. (Committee Member)
Jack Rubinstein, M.D. (Committee Member)
207 p.

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Citations

  • Essandoh, K. (2019). The Role of Tsg101 in the Development of Physiological Cardiac Hypertrophy and Cardio-Protection from Endotoxin-Induced Cardiac Dysfunction [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563526987921154

    APA Style (7th edition)

  • Essandoh, Kobina. The Role of Tsg101 in the Development of Physiological Cardiac Hypertrophy and Cardio-Protection from Endotoxin-Induced Cardiac Dysfunction. 2019. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563526987921154.

    MLA Style (8th edition)

  • Essandoh, Kobina. "The Role of Tsg101 in the Development of Physiological Cardiac Hypertrophy and Cardio-Protection from Endotoxin-Induced Cardiac Dysfunction." Doctoral dissertation, University of Cincinnati, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563526987921154

    Chicago Manual of Style (17th edition)