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.
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.
|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|
|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|
|Okada, Hideshi; Lai, N Chin; Kawaraguchi, Yoshitaka et al. (2013) Integrins protect cardiomyocytes from ischemia/reperfusion injury. J Clin Invest 123:4294-308|
|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|
|Pott, Christian; Eckardt, Lars; Goldhaber, Joshua I (2011) Triple threat: the Na+/Ca2+ exchanger in the pathophysiology of cardiac arrhythmia, ischemia and heart failure. Curr Drug Targets 12:737-47|
|Neco, Patricia; Rose, Beth; Huynh, Nhi et al. (2010) Sodium-calcium exchange is essential for effective triggering of calcium release in mouse heart. Biophys J 99:755-64|
|Goldhaber, Joshua I; Hamilton, Michele A (2010) Role of inotropic agents in the treatment of heart failure. Circulation 121:1655-60|
|Goldhaber, Joshua I; Bridge, John H B (2009) Loss of intracellular and intercellular synchrony of calcium release in systolic heart failure. Circ Heart Fail 2:157-9|
|Chantawansri, Chana; Huynh, Nhi; Yamanaka, Jun et al. (2008) Effect of metabolic inhibition on couplon behavior in rabbit ventricular myocytes. Biophys J 94:1656-66|
|Pott, Christian; Henderson, Scott A; Goldhaber, Joshua I et al. (2007) Na+/Ca2+ exchanger knockout mice: plasticity of cardiac excitation-contraction coupling. Ann N Y Acad Sci 1099:270-5|
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