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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Przywara, Dennis
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Cedars-Sinai Medical Center
Los Angeles
United States
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Shimizu, Hirohito; Schredelseker, Johann; Huang, Jie et al. (2015) Mitochondrial Ca(2+) uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity. Elife 4:
Torrente, Angelo G; Zhang, Rui; Zaini, Audrey et al. (2015) Burst pacemaker activity of the sinoatrial node in sodium-calcium exchanger knockout mice. Proc Natl Acad Sci U S A 112:9769-74
Kapoor, Nidhi; Tran, Andrew; Kang, Jeanney et al. (2015) Regulation of calcium clock-mediated pacemaking by inositol-1,4,5-trisphosphate receptors in mouse sinoatrial nodal cells. J Physiol 593:2649-63
Torres, Natalia S; Sachse, Frank B; Izu, Leighton T et al. (2014) A modified local control model for Ca2+ transients in cardiomyocytes: junctional flux is accompanied by release from adjacent non-junctional RyRs. J Mol Cell Cardiol 68:1-11
Anderson, Mark E; Goldhaber, Joshua; Houser, Steven R et al. (2014) Embryonic stem cell-derived cardiac myocytes are not ready for human trials. Circ Res 115:335-8
Ottolia, Michela; Torres, Natalia; Bridge, John H B et al. (2013) Na/Ca exchange and contraction of the heart. J Mol Cell Cardiol 61:28-33
Schwab, Bettina C; Seemann, Gunnar; Lasher, Richard A et al. (2013) Quantitative analysis of cardiac tissue including fibroblasts using three-dimensional confocal microscopy and image reconstruction: towards a basis for electrophysiological modeling. IEEE Trans Med Imaging 32:862-72
Goldhaber, Joshua I; Philipson, Kenneth D (2013) Cardiac sodium-calcium exchange and efficient excitation-contraction coupling: implications for heart disease. Adv Exp Med Biol 961:355-64
Okada, Hideshi; Lai, N Chin; Kawaraguchi, Yoshitaka et al. (2013) Integrins protect cardiomyocytes from ischemia/reperfusion injury. J Clin Invest 123:4294-308
Pott, Christian; Muszynski, Adam; Ruhe, Matthias et al. (2012) Proarrhythmia in a non-failing murine model of cardiac-specific Na+/Ca 2+ exchanger overexpression: whole heart and cellular mechanisms. Basic Res Cardiol 107:247

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