Uncoupling Protein-2 Modulates Myocardial Excitation-Contraction Coupling
Rationale: Uncoupling protein (UCP)2 is a mitochondrial inner membrane protein that is expressed in mammalian myocardium under normal conditions and upregulated in pathological states such as heart failure. UCP2 is thought to protect cardiomyocytes against oxidative stress by dissipating the mitochondrial proton gradient and mitochondrial membrane potential (Î”Î¨m), thereby reducing mitochondrial reactive oxygen species generation. However, in apparent conflict with its uncoupling role, UCP2 has also been proposed to be essential for mitochondrial Ca2+ uptake, which could have a protective action by stimulating mitochondrial ATP production. Objective: The goal of this study was to better understand the role of myocardial UCP2 by examining the effects of UCP2 on bioenergetics, Ca2+ homeostasis, and excitation-contraction coupling in neonatal cardiomyocytes. Methods and Results: Adenoviral-mediated expression of UCP2 caused a mild depression of Î”Î¨m and increased the basal rate of oxygen consumption but did not affect total cellular ATP levels. Mitochondrial Ca2+ uptake was examined in permeabilized cells loaded with the mitochondria-selective Ca2+ probe, rhod-2. UCP2 overexpression markedly inhibited mitochondrial Ca2+ uptake. Pretreatment with the UCP2-specific inhibitor genipin largely reversed the effects UCP2 expression on mitochondrial Ca2+ handling, bioenergetics, and oxygen utilization. Electrically evoked cytosolic Ca 2+ transients and spontaneous cytosolic Ca2+ sparks were examined using fluo-based probes and confocal microscopy in line scan mode. UCP2 overexpression significantly prolonged the decay phase of [Ca2+]c transients in electrically paced cells, increased [Ca2+]c spark activity and increased the probability that Ca2+ sparks propagated into Ca2+ waves. This dysregulation results from a loss of the ability of mitochondria to suppress local Ca2+-induced Ca 2+ release activity of the sarcoplasmic reticulum. Conclusion: Increases in UCP2 expression that lower Î”Î¨m and contribute to protection against oxidative stress, also have deleterious effects on beat-to-beat [Ca2+]c handling and excitation-contraction coupling, which may contribute to the progression of heart disease. Â© 2010 American Heart Association. All rights reserved.
Digital Object Identifier (DOI)
Turner, Jay D.; Gaspers, Lawrence D.; Wang, Guoqiang; and Thomas, Andrew P., "Uncoupling Protein-2 Modulates Myocardial Excitation-Contraction Coupling" (2010). Neurosurgery. 498.