The overall aim of the proposed research is to identify the cellular mechanisms responsible for the abnormalities in intracellular calcium handling observed with cardiac hypertrophy and its progression to heart failure. Despite extensive investigations establishing abnormalities in intracellular calcium ([Ca2+]i) regulation with cardiac hypertrophy, the specific cellular mechanisms responsible for these abnormalities remain unknown. Recently, the focal, non-propagating release of Ca2+, from the sarcoplasmic reticulum (SR) via the ryanodine receptor (i.e. Local [Ca2+]i transients, Ca2+ sparks) has been observed in response to Ca2+ entry through L-type Ca2+ channels. New methods in laser scanning confocal microscopy will be coupled with classic cellular electrophysiological techniques to identify the cellular process(es) responsible for the abnormalities of Ca2+ handling observed with cardiac hypertrophy.
The specific aims are: 1) test the hypothesis that alterations in the amplitude of the [Ca2+]i transient with cardiac hypertrophy are due to alterations in the release of Ca2+ by the ryanodine receptor in the SR, 2) test the hypothesis that the prolongation of the [Ca2+]i transients observed with cardiac hypertrophy is due to an increase in the duration of Ca2+ sparks from the SR which in turn reflects a decrease in the reuptake of Ca2+ by the SR Ca2+-ATPase. 3) test the hypothesis that the increase in resting [Ca2+]i seen with cardiac hypertrophy is due to either an increase in the amplitude, probability of observing, or duration of Ca2+ sparks at rest. The studies will define, for the first time, the abnormalities in the elemental events of excitation-contraction coupling (i.e. Ca 2+ sparks at individual sarcomeres in the region of the ryanodine receptor) in a pathologic model which is remarkably similar to cardiac hypertrophy and heart failure in humans. This information is essential for the development of new and novel treatment strategies such as gene therapy.
| Aggarwal, R; Shorofsky, S R; Goldman, L et al. (1997) Tetrodotoxin-blockable calcium currents in rat ventricular myocytes; a third type of cardiac cell sodium current. J Physiol 505 ( Pt 2):353-69 |
