REPOLARIZATION AND REMODELING IN THE MAMMALIAN HEART

Summary

Principal Investigator: JEANNE NERBONNE
Abstract: 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.
Funding Period: 2000-09-30 - 2010-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Calmodulin kinase II inhibition shortens action potential duration by upregulation of K+ currents
    Jingdong Li
    Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, USA
    Circ Res 99:1092-9. 2006
  2. pmc Homeostatic regulation of electrical excitability in physiological cardiac hypertrophy
    Kai Chien Yang
    Department of Developmental Biology, Washington University Medical School, St Louis, MO 63110 1093, USA
    J Physiol 588:5015-32. 2010
  3. pmc MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts
    Scot J Matkovich
    Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
    Circ Res 106:166-75. 2010
  4. pmc Palmitate attenuates myocardial contractility through augmentation of repolarizing Kv currents
    Todd E Haim
    Pfizer Global Research and Development, Chesterfield, MO 63017, USA
    J Mol Cell Cardiol 48:395-405. 2010
  5. pmc Molecular determinants of cardiac transient outward potassium current (I(to)) expression and regulation
    Noriko Niwa
    Department of Developmental Biology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8103, St Louis, MO 63110 1093, USA
    J Mol Cell Cardiol 48:12-25. 2010
  6. ncbi Mechanisms linking short- and long-term electrical remodeling in the heart...is it a stretch?
    Scott B Marrus
    Department of Internal Medicine, Washington University Medical School, Saint Louis, Missouri, USA
    Channels (Austin) 2:117-24. 2008
  7. ncbi Calmodulin kinase II inhibition enhances ischemic preconditioning by augmenting ATP-sensitive K+ current
    Jingdong Li
    Departments of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242 1081, USA
    Channels (Austin) 1:387-94. 2007
  8. pmc PPARalpha-mediated remodeling of repolarizing voltage-gated K+ (Kv) channels in a mouse model of metabolic cardiomyopathy
    Celine Marionneau
    Department of Molecular Biology and Pharmacology, Washington University Medical School, St Louis, MO 63110, USA
    J Mol Cell Cardiol 44:1002-15. 2008
  9. pmc Distinct cellular and molecular mechanisms underlie functional remodeling of repolarizing K+ currents with left ventricular hypertrophy
    Celine Marionneau
    Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO 63110, USA
    Circ Res 102:1406-15. 2008
  10. pmc Kv4.3 is not required for the generation of functional Ito,f channels in adult mouse ventricles
    Noriko Niwa
    Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8103, St Louis, MO 63110 1093, USA
    J Mol Cell Cardiol 44:95-104. 2008

Detail Information

Publications12

  1. ncbi Calmodulin kinase II inhibition shortens action potential duration by upregulation of K+ currents
    Jingdong Li
    Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, USA
    Circ Res 99:1092-9. 2006
    ..These findings provide novel in vivo and cellular evidence that CaMKII links Ca(2+)(i) to cardiac repolarization and suggest that PLN may be a critical CaMKII target for feedback regulation of APD in ventricular myocytes...
  2. pmc Homeostatic regulation of electrical excitability in physiological cardiac hypertrophy
    Kai Chien Yang
    Department of Developmental Biology, Washington University Medical School, St Louis, MO 63110 1093, USA
    J Physiol 588:5015-32. 2010
    ....
  3. pmc MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts
    Scot J Matkovich
    Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
    Circ Res 106:166-75. 2010
    ..Because miR-133a levels decrease during reactive cardiac hypertrophy, some have considered that restoring miR-133a levels could suppress hypertrophic remodeling...
  4. pmc Palmitate attenuates myocardial contractility through augmentation of repolarizing Kv currents
    Todd E Haim
    Pfizer Global Research and Development, Chesterfield, MO 63017, USA
    J Mol Cell Cardiol 48:395-405. 2010
    ..Taken together, these results suggest that elevations in circulating saturated free fatty acids, as occurs in diabetes, can directly augment repolarizing myocardial Kv currents and impair excitation-contraction coupling...
  5. pmc Molecular determinants of cardiac transient outward potassium current (I(to)) expression and regulation
    Noriko Niwa
    Department of Developmental Biology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8103, St Louis, MO 63110 1093, USA
    J Mol Cell Cardiol 48:12-25. 2010
    ....
  6. ncbi Mechanisms linking short- and long-term electrical remodeling in the heart...is it a stretch?
    Scott B Marrus
    Department of Internal Medicine, Washington University Medical School, Saint Louis, Missouri, USA
    Channels (Austin) 2:117-24. 2008
    ..With time, altered gene transcription and protein synthesis lead to persistent changes in ion channel levels and activities, changes that can significantly impact normal cardiac function and increase arrhythmia susceptibility...
  7. ncbi Calmodulin kinase II inhibition enhances ischemic preconditioning by augmenting ATP-sensitive K+ current
    Jingdong Li
    Departments of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242 1081, USA
    Channels (Austin) 1:387-94. 2007
    ..Our study results show CaMKII inhibition enhances beneficial effects of IP by increasing I(KATP)...
  8. pmc PPARalpha-mediated remodeling of repolarizing voltage-gated K+ (Kv) channels in a mouse model of metabolic cardiomyopathy
    Celine Marionneau
    Department of Molecular Biology and Pharmacology, Washington University Medical School, St Louis, MO 63110, USA
    J Mol Cell Cardiol 44:1002-15. 2008
    ..The molecular mechanisms underlying I(to,f) and I(ss) remodeling in MHC-PPARalpha ventricular myocytes, therefore, are distinct...
  9. pmc Distinct cellular and molecular mechanisms underlie functional remodeling of repolarizing K+ currents with left ventricular hypertrophy
    Celine Marionneau
    Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO 63110, USA
    Circ Res 102:1406-15. 2008
    ..Functional changes in repolarizing K(+) currents with LVH, therefore, result from distinct cellular (cardiomyocyte enlargement) and molecular (alterations in the numbers of functional channels) mechanisms...
  10. pmc Kv4.3 is not required for the generation of functional Ito,f channels in adult mouse ventricles
    Noriko Niwa
    Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8103, St Louis, MO 63110 1093, USA
    J Mol Cell Cardiol 44:95-104. 2008
    ..3-/- ventricles. Taken together, the results presented here suggest that, in contrast with Kv4.2, Kv4.3 is not required for the generation of functional mouse ventricular I(to,f) channels...
  11. pmc Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT
    Barry London
    University of Pittsburgh, Cardiovascular Institute, Pittsburgh, PA 15213, USA
    J Physiol 578:115-29. 2007
    ..2DN mice. Thus, dispersion of repolarization (DR) appears to be an important determinant of arrhythmia vulnerability...
  12. pmc Deep RNA sequencing reveals dynamic regulation of myocardial noncoding RNAs in failing human heart and remodeling with mechanical circulatory support
    Kai Chien Yang
    Department of Developmental Biology K C Y, J M N and Center for Cardiovascular Research, Division of Cardiology, Department of Internal Medicine K A Y, A Y P, V K T, G A E, D L M, Washington University Medical School, St Louis, MO Division of Cardiothoracic Surgery, New York Presbyterian Hospital, Columbia University College of Physicians and Surgeons, New York, NY I G and Department of Surgery, University of Maryland School of Medicine, Baltimore F H C Dr Yang s current affiliation is the Department of Pharmacology, National Taiwan University School of Medicine, Taipei, Taiwan
    Circulation 129:1009-21. 2014
    ....