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 life-threatening cardiac arrhythmias. Considerable evidence has accumulated to suggest that """"""""electrical remodelling"""""""" occurs in the hypertrophied heart and that this reflects, at least in part, changes in the xpression and/or the properties of the voltage-gated K+ (Kv) currents that underlie myocardial action potential repolarization. The mechanisms involved in Kv channel remodeling in the hypertrophied ventricular myocardium, however, have not been delineated. The experiments proposed here will explore directly the molecular mechanisms underlying Kv channel remodeling in a mouse model of pressure overload-induced left ventricular hypertrophy (LVH). Regional differences in the effects of LVH on the functional expression, the properties and/or the distributions of ventricular Kv channels, particularly the transient outward K+ channels, I(to,f) will be determined, and experiments focused on delineating the roles of elevated intracellular Ca2+, Kv channel accessory subunits (KChIP2 and Kv-beta1) and the actin cytoskeleton in regulating functional I(to,f) channel expression will be completed. 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 Kv channels, as well as into the molecular mechanisms underlying """"""""electrical remodelling"""""""" 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 #
2R01HL066388-05A1
Application #
6921850
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Lathrop, David A
Project Start
2000-09-30
Project End
2009-03-31
Budget Start
2005-04-15
Budget End
2006-03-31
Support Year
5
Fiscal Year
2005
Total Cost
$382,500
Indirect Cost
Name
Washington University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
068552207
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

Showing the most recent 10 out of 24 publications