Abstract
There is mounting evidence to suggest that protein glutathionylation is a key process contributing to the development of pathology. Glutathionylation occurs as a result of posttranslational modification of a protein and involves the addition of a glutathione moiety at cysteine residues. Such modification can occur on a number of proteins, and exerts a variety of functional consequences. The L-type Ca2+ channel has been identified as a glutathionylation target that participates in the development of cardiac pathology. Ca2+ influx via the L-type Ca2+ channel increases production of mitochondrial reactive oxygen species (ROS) in cardiomyocytes during periods of oxidative stress. This induces a persistent increase in channel open probability, and the resulting constitutive increase in Ca2+ influx amplifies the cross-talk between the mitochondria and the channel. Novel strategies utilising targeted peptide delivery to uncouple mitochondrial ROS and Ca2+ flux via the L-type Ca2+ channel following ischemia-reperfusion have delivered promising results, and have proven capable of restoring appropriate mitochondrial function in myocytes and in vivo.
Highlights
Oxidative stress is a key feature underlying many different forms of cardiac pathology and represents an imbalance between the production of reactive oxygen species (ROS) and the cell’s inherent antioxidant defense system [1]
In order to further elucidate the interaction between the L-type Ca2+ channel and mitochondrial ROS production, we investigated the effect of a transient exposure of guinea pig cardiac myocytes to a concentration of H2O2 that was insufficient to induce apoptosis or necrosis, but mimicked an ischemia/reperfusion (I/R) injury, in which return of blood flow to the ischemic heart during reperfusion induces a burst of ROS [40]
Calcium influx via the L-type calcium channel is the predominant means of calcium entry into cardiomyocytes and provides the trigger for appropriate excitation contraction in the heart
Summary
Oxidative stress is a key feature underlying many different forms of cardiac pathology and represents an imbalance between the production of reactive oxygen species (ROS) and the cell’s inherent antioxidant defense system [1]. Calcium is vital for cardiac excitation-contraction coupling, but is a key regulator of mitochondrial ROS production. The interplay between ROS and Ca2+ in cardiomyocytes is a critical determinant of cardiac function [10,11]. Ca2+ in mediating cardiac pathology will be examined, and particular emphasis will be placed on ROS-dependent changes in L-type Ca2+ channel function including glutathionylation. The use of novel interventions to alleviate the effects of oxidative stress-induced changes in L-type calcium channel function will be discussed. 2. The Role of Calcium and Reactive Oxygen Species (ROS) in Oxidative Stress Responses
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