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University of Cincinnati

1. Gardner, George. The Functional Role of Hsp20 in the Heart.

Degree: PhD, Medicine: Molecular, Cellular and Biochemical Pharmacology, 2018, University of Cincinnati

In this dissertation, the cardiac effects of two functional alterations in the heat shock protein 20 (Hsp20), its phosphorylation at Ser16 and a human S10F mutation, were determined. Hsp20 has been shown to be a critical regulator of cardiomyocyte survival upon cardiac stress as well as a regulator of Ca2+-cycling and cardiac function. In addition, the PKA phosphorylation of Hsp20 is is highly elevated in human heart failure. Previous studies demonstrated that this phosphorylation is associated with cardioprotection in infected cardiomyocytes. In this dissertation, it was further demonstrated that acute increases in constitutively phosphorylated Hsp20 (S16D) enhance cardiomyocyte contractility to a greater extent that WT-Hsp20 in rat cardiomyocytes. However, non-phosphorylatable Hsp20 (S16A) abolishes these stimulatory effects on contractility, indicating a dual beneficial role for phosphorylated (S16D) Hsp20. To determine the functional significance and long-term effects of increased Hsp20 phosphorylation in vivo, transgenic mice with cardiac-specific overexpression of constitutively phosphorylated Hsp20 (S16D-Hsp20) were generated and a line with similar levels, as those in human failing hearts, was characterized. In contrast to the findings in rat cardiomyocytes, S16D-Hsp20 transgenic mice exhibited early fibrotic remodeling, which culminated in left ventricular dysfunction, heart failure and early death. Early fibrosis was associated with translocation of S16D-Hsp20 to the nucleus and formation of an Hsp20/NF-?B/STAT3 nuclear complex, leading to upregulation of interleukin 6 (IL6) in the cardiomyocytes. Secretion of IL6 from the S16D cells resulted in paracrine activation of fibroblasts, evidenced by enhanced proliferation and upregulation of collagens and cytokines, through phosphorylated STAT3. These effects were specific to S16D as parallel studies with S16A cardiomyocytes did not elicit similar results. Furthermore, the pro-fibrotic effects of S16D were abrogated by an IL6-neutralizing antibody in isolated cells, and treatment of the S16D mice with an IL6 receptor antagonist antibody (MR16-1) inhibited the development of fibrosis and preserved left ventricular function. Furthermore, the effects of the S10F-Hsp20 human mutation on cardiac function and remodeling were assessed in female transgenic mice. Previous findings showed that cardiac-specific overexpression of this mutant was associated with reduced autophagy, left ventricular dysfunction and early death in male mice. However, the present study indicates that females have normal function with no alterations in autophagy except they invariably died after one to four pregnancies. Further examination of mutant females, following three pregnancies, revealed pathological hypertrophic remodeling, associated with left ventricular chamber dilation and dysfunction. Subsequent studies revealed that cardiomyocyte apoptosis was elevated in mutant female hearts after the third delivery, associated with decreases in the levels of Bcl-2/Bax and Akt phosphorylation.… Advisors/Committee Members: Kranias, Evangelia (Committee Chair).

Subjects/Keywords: Molecular Biology; Hsp20; heart failure; cardiomyocyte; fibroblast; fibrosis; IL6

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APA (6th Edition):

Gardner, G. (2018). The Functional Role of Hsp20 in the Heart. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin153538225667606

Chicago Manual of Style (16th Edition):

Gardner, George. “The Functional Role of Hsp20 in the Heart.” 2018. Doctoral Dissertation, University of Cincinnati. Accessed November 20, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin153538225667606.

MLA Handbook (7th Edition):

Gardner, George. “The Functional Role of Hsp20 in the Heart.” 2018. Web. 20 Nov 2018.

Vancouver:

Gardner G. The Functional Role of Hsp20 in the Heart. [Internet] [Doctoral dissertation]. University of Cincinnati; 2018. [cited 2018 Nov 20]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin153538225667606.

Council of Science Editors:

Gardner G. The Functional Role of Hsp20 in the Heart. [Doctoral Dissertation]. University of Cincinnati; 2018. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin153538225667606

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