Calcium Signaling, Metabolism, and EC Coupling in Heart
Principal Investigator: Joshua I Goldhaber
Affiliation: Cedars-Sinai Medical Center
Abstract: DESCRIPTION (provided by applicant): The applicant's long-term aims are to continue studies on calcium signaling, excitation-contraction (EC) coupling, and the dependence of these processes on energy metabolism in cardiac muscle. The specific aims are to study ventricular cells from rabbits and mice (including cardiac-specific sodium-calcium exchanger knock-out mice) to: 1) investigate calcium signaling and EC coupling in remodeled cells from the peri-infarct zone in rabbits. This will include an assessment of whether loss of L-type calcium channel function can account for failure of EC coupling and whether significant alterations in the 3-dimensional structure and spatial distribution of transverse-tubules, ryanodine and dihydropyridine receptors are involved in the failure of these cells;2) investigate the effect of metabolic inhibition on the function and structure of couplons in rabbit ventricular myocytes. This will include a measurement of the minimum number of L-type calcium channels in a couplon and the way that metabolic inhibition affects their function. In particular, alterations in calcium spark and spike formation and cellular micro-architecture of the transverse-tubule system as a cause of the functional loss of couplons during metabolic inhibition will be considered;3) study the resistance of sodium-calcium exchanger knock-out mice to metabolic stress. This will include an investigation of the hypothesis that metabolic inhibition prevents activation of reverse sodium-calcium exchange in wild-type mice, resulting in disruption of the calcium-induced calcium release mechanism of EC coupling. In contrast, it is hypothesized that sodium-calcium exchanger knock-out mice do not require sodium-calcium exchange for EC coupling and are therefore resistant to the effects of metabolic inhibition. The consequences of inhibiting sodium-calcium exchange activation on calcium spike latency will be examined. These experiments are, among other things, designed to explain the importance of diadic cleft calcium in the trigger process. Methods include measuring calcium spike probabilities and their latency distributions in rabbits and mice before and after treatment with metabolic inhibitors or controlled myocardial infarction. In addition the methods include recently developed procedures for reconstructing the 3-dimensional architecture of the transverse-tubule system and the 3- dimensional distribution of ryanodine and dihydropyridine receptors in peri-infarct cells and cells treated with metabolic inhibitors. PUBLIC HEALTH RELEVANCE: The investigators are studying the basic aspects of heart muscle contraction using single heart cells. The purpose of this work is to determine the exact mechanisms responsible for weakening of the heart muscle during heart attacks and in patients with heart failure. This will lead to new therapeutic strategies for preserving heart muscle function, thereby reducing the incidence of heart failure.
Funding Period: ----------------2002 - ---------------2014-
more information: NIH RePORT
- Effect of metabolic inhibition on couplon behavior in rabbit ventricular myocytesChana Chantawansri
Division of Cardiology, Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
Biophys J 94:1656-66. 2008..In addition, the results are consistent with loss of RyR activity, which can be mitigated under conditions likely to enlarge the trigger...
- Na/Ca exchange and contraction of the heartMichela Ottolia
Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
J Mol Cell Cardiol 61:28-33. 2013..This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes". ..
- Quantitative analysis of cardiac tissue including fibroblasts using three-dimensional confocal microscopy and image reconstruction: towards a basis for electrophysiological modelingBettina C Schwab
Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA
IEEE Trans Med Imaging 32:862-72. 2013..We suggest that the presented methodology provides an important contribution to modeling normal and diseased tissue. Applications of the methodology include the clinical characterization of disease-associated remodeling...
- Cardiac sodium-calcium exchange and efficient excitation-contraction coupling: implications for heart diseaseJoshua I Goldhaber
Cedars Sinai Heart Institute, Los Angeles, CA 90048, USA
Adv Exp Med Biol 961:355-64. 2013..Thus, our data support the conclusion that NCX is an important regulator of cardiac contractility. These findings suggest that manipulation of NCX may be beneficial in the treatment of heart failure...
- Characterization and therapeutic potential of induced pluripotent stem cell-derived cardiovascular progenitor cellsAli Nsair
Department of Medicine and Physiology, Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
PLoS ONE 7:e45603. 2012..Study of endogenous and induced pluripotent stem cell (iPSC)-derived CPCs has been limited due to the lack of specific cell surface markers to isolate them and conditions for their in vitro expansion that maintain their multipotency...
- Proarrhythmia in a non-failing murine model of cardiac-specific Na+/Ca 2+ exchanger overexpression: whole heart and cellular mechanismsChristian Pott
Division of Experimental and Clinical Electrophysiology, Department of Cardiology and Angiology, University Hospital Munster, Munster, Germany
Basic Res Cardiol 107:247. 2012..The underlying mechanisms are: (1) occurrence of EADs due to delayed repolarization; (2) facilitated translation from sCR into DADs; (3) proneness to sCR possibly caused by altered Ca(2+) handling and/or increased RyR expression...
- Na+ currents are required for efficient excitation-contraction coupling in rabbit ventricular myocytes: a possible contribution of neuronal Na+ channelsNatalia S Torres
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112 5000, USA
J Physiol 588:4249-60. 2010..The results can be explained if non-linearities in excitation-contraction coupling mechanisms modify the coupling fidelity of ICa, which is known to be low at positive potentials...
- Activation of reverse Na+-Ca2+ exchange by the Na+ current augments the cardiac Ca2+ transient: evidence from NCX knockout miceRobert Larbig
Cardiovascular Research Laboratories, MRL 3 645, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1760, USA
J Physiol 588:3267-76. 2010..This is an important mechanism for regulation of Ca(2+) release and contractility in murine heart...
- Spontaneously beating cardiomyocytes derived from white mature adipocytesMedet Jumabay
David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1679, USA
Cardiovasc Res 85:17-27. 2010..The objective of this study was to examine if white adipocytes would be able to supply cardiomyocytes...
- A modified local control model for Ca(2+) transients in cardiomyocytes: Junctional flux is accompanied by release from adjacent non-junctional RyRsNatalia S Torres
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, 95S 2000E, Salt Lake City, UT 84112, USA
J Mol Cell Cardiol 68:1-11. 2014..We believe that this model will be useful for describing excitation-contraction coupling in cardiac myocytes with a sparse t-system, which includes those from diseased heart tissue as well as atrial myocytes of some species. ..
- Triple threat: the Na+/Ca2+ exchanger in the pathophysiology of cardiac arrhythmia, ischemia and heart failureChristian Pott
University Hospital of Muenster, Department of Cardiology and Angiology, Albert Schweitzer Str 33, 48149 Muenster, Germany
Curr Drug Targets 12:737-47. 2011..Transgenic mice as well as pharmacological interventions have been used to support the idea of using NCX inhibition as a future pharmacological strategy to treat cardiovascular disease...
- Sodium-calcium exchange is essential for effective triggering of calcium release in mouse heartPatricia Neco
Departments of Medicine Cardiology and Physiology and the Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
Biophys J 99:755-64. 2010..Thus, reducing subsarcolemmal Ca2+ with EGTA in NCX KO mice reveals the dependence of Ca2+ release on NCX...