It is well documented that membrane excitability and excitation-contraction coupling are altered in the hypertrophied heart and that ventricular hypertrophy is a risk factor for the development of arrhythmias. Considerable evidence has accumulated to suggest that """"""""electrical remodeling"""""""" occurs in the hypertrophied heart and that this reflects, at least in part, changes in the expression/properties of repolarizing, voltage-gated K+ currents. The experiments proposed here will test this hypothesis directly in a mouse model of pressure overload-induced left ventricular hypertrophy. The functional consequences of hypertrophy on the properties and distributions of ventricular voltage-gated K+ channels will be determined, and experiments focused on exploring the molecular mechanisms underlying """"""""electrical remodeling"""""""" of voltage-gated K+ channels in these cells will be completed. In addition, transgenic and targeted deletion strategies will be exploited to test the specific hypotheses that there are two, molecularly distinct, components of (mouse ventricular) IK,slow and that alpha subunits of the Kv 3 subunits underlie (mouse ventricular) Iss. A sophisticated combination of electrophysiological, biochemical, molecular genetic, immunohistochemical and imaging techniques will be exploited in mice to achieve the stated aims of this proposal. We anticipate that the studies outlined here will provide fundamentally important new insights into the effects of pressure overload-induced left ventricular hypertrophy on repolarizing voltage-gated K+ channels, as well as into the molecular mechanisms underlying """"""""electrical remodeling"""""""" in the hypertrophied heart. In the long term, these insights should translate into more effective treatment strategies to reduce the risk of sudden death and the mortality and morbidity associated with myocardial hypertrophy and failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066388-03
Application #
6527712
Study Section
Special Emphasis Panel (ZHL1-CSR-O (S1))
Program Officer
Lathrop, David A
Project Start
2000-09-30
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$308,000
Indirect Cost
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Johnson, Eric K; Matkovich, Scot J; Nerbonne, Jeanne M (2018) Regional Differences in mRNA and lncRNA Expression Profiles in Non-Failing Human Atria and Ventricles. Sci Rep 8:13919
Johnson, Eric K; Springer, Steven J; Wang, Wei et al. (2018) Differential Expression and Remodeling of Transient Outward Potassium Currents in Human Left Ventricles. Circ Arrhythm Electrophysiol 11:e005914
Hueneke, Rocco; Adenwala, Adam; Mellor, Rebecca L et al. (2017) Early remodeling of repolarizing K+ currents in the ?MHC403/+ mouse model of familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 103:93-101
Yang, Kai-Chien; Nerbonne, Jeanne M (2016) Mechanisms contributing to myocardial potassium channel diversity, regulation and remodeling. Trends Cardiovasc Med 26:209-18
Yang, Kai-Chien; Yamada, Kathryn A; Patel, Akshar Y et al. (2014) Deep RNA sequencing reveals dynamic regulation of myocardial noncoding RNAs in failing human heart and remodeling with mechanical circulatory support. Circulation 129:1009-21
Nerbonne, Jeanne M (2011) Repolarizing cardiac potassium channels: multiple sites and mechanisms for CaMKII-mediated regulation. Heart Rhythm 8:938-41
Yang, Kai-Chien; Foeger, Nicholas C; Marionneau, Celine et al. (2010) Homeostatic regulation of electrical excitability in physiological cardiac hypertrophy. J Physiol 588:5015-32
Fishman, Glenn I; Chugh, Sumeet S; Dimarco, John P et al. (2010) Sudden cardiac death prediction and prevention: report from a National Heart, Lung, and Blood Institute and Heart Rhythm Society Workshop. Circulation 122:2335-48
Matkovich, Scot J; Wang, Wei; Tu, Yizheng et al. (2010) MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts. Circ Res 106:166-75
Haim, Todd E; Wang, Wei; Flagg, Thomas P et al. (2010) Palmitate attenuates myocardial contractility through augmentation of repolarizing Kv currents. J Mol Cell Cardiol 48:395-405

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