Skip to Main Content
Frequently Asked Questions
Submit an ETD
Global Search Box
Need Help?
Keyword Search
Participating Institutions
Advanced Search
School Logo
Files
File List
ucin1148396901.pdf (5.58 MB)
ETD Abstract Container
Abstract Header
TRANSCRIPTIONAL REGULATION OF CARDIAC HYPERTROPHY AND HEART FAILURE
Author Info
XU, JIAN
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1148396901
Abstract Details
Year and Degree
2006, PhD, University of Cincinnati, Medicine : Molecular, Cellular and Biochemical Pharmacology.
Abstract
Cardiac hypertrophy and dilatation are mediated by neuro-endocrine factors, internal stretch and stress sensitive signaling pathways, which in turn transduce alterations in cardiac gene expression through specific transcription factors. This dissertation will, in the first section, provide direct evidence for transcription factor myocyte enhancer factor 2 (MEF2) in the regulation of cardiac dilation and fibrosis through reprogramming cardiac gene expression; in the second section, introduce a novel secreted factor growth differentiation factor 15 (GDF15) as a cardiac anti-hypertrophic and protective factor. The MEF2 family of transcription factors have been indirectly implicated as a downstream mediator of hypertrophic signaling pathways. In this dissertation, we demonstrate directly that MEF2 induce dilated cardiomyopathy and the lengthening of myocytes without a primary induction of cardiac hypertrophy. Cardiac-specific overexpression of MEF2A or MEF2C showed spontaneous cardiomyopathy, which was not altered by activated calcineurin, or developed more fulminant disease following pressure overload. In cultured cardiomyocytes, MEF2A and MEF2C overexpression induced sarcomeric disorganization and focal elongation. Mechanistically, MEF2A and MEF2C programmed similar alteration in gene expression that included extracellular matrix remodeling, ion handling, and metabolic genes. Indeed, cultured cardiomyocytes overexpressing MEF2A, or adult myocytes from MEF2A transgenic hearts, showed reduced transient outward currents, suggesting a proximal mechanism underlying MEF2-dependent cardiomyopathy. During the analysis of gene reprogramming by MEF2, we noted dramatic induction of GDF15. GDF15 is induced by conditions that promote hypertrophy and dilation. Transgenic mice with cardiac-specific overexpression of GDF15 were normal, but were partially resistant to induced hypertrophy. GDF15 antagonized induced hypertrophy in cultured cardiomyocyte. Transient expression of GDF15 by intravenous adenoviral delivery, or by direct injection of recombinant protein, attenuated ventricular dilation and heart failure in MLP null mice through an endocrine effect. Conversely, Gdf15 null mice showed enhanced cardiac hypertrophic growth, and a pronounced loss in ventricular performance following stimulation. Mechanistically, GDF15 promoted activation of Smad2/3, which was partially responsible for the anti-hypertrophic effects. These results identify GDF15 as a novel endocrine factor that antagonizes the hypertrophic response and loss of ventricular performance.
Committee
Dr. Jeffery Molkentin (Advisor)
Pages
241 p.
Keywords
MEF2
;
GDF-15/MIC-1
;
cardiac hypertrophy
;
heart failure
;
dilated cardiomyopathy
;
transcription factor
;
smad
Recommended Citations
Refworks
EndNote
RIS
Mendeley
Citations
XU, J. (2006).
TRANSCRIPTIONAL REGULATION OF CARDIAC HYPERTROPHY AND HEART FAILURE
[Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1148396901
APA Style (7th edition)
XU, JIAN.
TRANSCRIPTIONAL REGULATION OF CARDIAC HYPERTROPHY AND HEART FAILURE.
2006. University of Cincinnati, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1148396901.
MLA Style (8th edition)
XU, JIAN. "TRANSCRIPTIONAL REGULATION OF CARDIAC HYPERTROPHY AND HEART FAILURE." Doctoral dissertation, University of Cincinnati, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1148396901
Chicago Manual of Style (17th edition)
Abstract Footer
Document number:
ucin1148396901
Download Count:
2,245
Copyright Info
© 2006, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.