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TRANSCRIPTIONAL REGULATION OF KV4.2 GENEBY IROQUOIS FAMILY PROTEINS

He, Wenjie (2009) TRANSCRIPTIONAL REGULATION OF KV4.2 GENEBY IROQUOIS FAMILY PROTEINS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Normal cardiac rhythms are generated by an organized propagation of depolarization and repolarization. The voltage-gated transient potassium current (Ito) is a major determinant of cardiac action potential. The Ito is expressed in a gradient across the left ventricular wall of the hearts, which is essential for the proper repolarization sequence in the left ventricle. Altered expression of Ito is seen in hypertrophied and failing hearts and may contribute to the increased incidence of cardiac sudden death. Thus, elucidating mechanisms underlying the expression of Ito channels will provide basic knowledge essential for the prevention and treatment of cardiac diseases with high public health significance.In the mammalian heart, Ito is produced by assembly of pore-forming Kv4 and accessory KChIP2 subunits. Differential expression of Kv4.2 gene underlies transmural gradient of Ito in the left ventricle in small rodents, whereas the size of Ito is correlated with different levels of KChIP2 in large animals. Recent studies have shown that atypical homeodomain Iroquois proteins are distributed in a gradient in the left ventricle and influence the expression of Kv4.2 and Ito. Therefore, this thesis examines the hypothesis that Irx proteins control Kv4.2 gene transcription in a cell-type specific manner and analyzes the underlying molecular mechanism. Irx3 and Irx5 are differentially expressed in a steep gradient in the left ventricle of rat hearts in an inverse pattern to Kv4.2 expression, whereas Irx4 is equally abundant in the ventricle. Irx5 activates Kv4.2 promoter in several non-myocyte cell lines, whereas the transcription factorinhibits the promoter activity in neonatal ventricular myocytes. Moreover, Irx4 prevents Irx5 to activate the channel promoter. Structure-function studies establish that the C-terminus of Irx5 is required for its regulation of channel promoter, whereas the N-terminus of Irx4 mediates its action. Addition of histone deacetylase inhibitor relieves the inhibitory effect of Irx4. Deletion and mutation analyses demonstrate the presence of a previously unidentified Irx5-responsive element in the Kv4.2 distant promoter region. Collectively, these results indicate that the interplay between Irx4 and Irx5 contributes to the heterogeneous expression of Kv4.2 gene, and hence Ito density, in the left ventricle of rat hearts.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
He, Wenjiehewenjie@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairTakimoto, Koichikoichi@pitt.eduKOICHI
Committee CoChairPitt, Brucebrucep@pitt.eduBRUCEP
Committee MemberBarchowsky, Aaronaab20@pitt.eduAAB20
Committee MemberWalker, Williamwalkerw@pitt.eduWALKERW
Date: 29 June 2009
Date Type: Completion
Defense Date: 26 January 2009
Approval Date: 29 June 2009
Submission Date: 30 March 2009
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Environmental and Occupational Health
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: KCND2
Other ID: http://etd.library.pitt.edu/ETD/available/etd-03302009-140301/, etd-03302009-140301
Date Deposited: 10 Nov 2011 19:33
Last Modified: 15 Nov 2016 13:37
URI: http://d-scholarship.pitt.edu/id/eprint/6652

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