Key result
Oxidative stress induces redox modifications of the ryanodine receptor (RyR2), leading to increased sarcoplasmic reticulum calcium leak that contributes to heart failure and arrhythmias.
Why the study?
Despite its clinical significance, molecular mechanisms of RyR dysfunction during oxidative stress are not fully understood.
Oxidative stress-induced redox modifications of the ryanodine receptor (RyR2) play a critical role in abnormal sarcoplasmic reticulum calcium leak, contributing to the pathogenesis of heart failure and arrhythmias.
Oxidative RyR2 modification may promote calcium leak in HF and arrhythmias; leaves open whether redox-targeted therapies alter outcomes.
Heart contraction vitally depends on tightly controlled intracellular Ca regulation. Because contraction is mainly driven by Ca released from the sarcoplasmic reticulum (SR), this organelle plays a particularly important role in Ca regulation. The type two ryanodine receptor (RyR2) is the major SR Ca release channel in ventricular myocytes. Several cardiac pathologies, including myocardial infarction and heart failure, are associated with increased RyR2 activity and diastolic SR Ca leak. It has been suggested that the increased RyR2 activity plays an important role in arrhythmias and contractile dysfunction. Several studies have linked increased SR Ca leak during myocardial infarction and heart failure to the activation of RyR2 in response to oxidative stress. This activation might include direct oxidation of RyR2 as well as indirect activation via phosphorylation or altered interactions with regulatory proteins. Out of ninety cysteine residues per RyR2 subunit, twenty one were reported to be in reduced state that could be potential targets for redox modifications that include S-nitrosylation, S-glutathionylation, and disulfide cross-linking. Despite its clinical significance, molecular mechanisms of RyR dysfunction during oxidative stress are not fully understood. Herein we review the most recent insights into redox-dependent modulation of RyR2 during oxidative stress and heart diseases.
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Nikolaienko et al. (2018) conducted a review in Heart diseases. Oxidative stress induces redox modifications of the ryanodine receptor (RyR2), leading to increased sarcoplasmic reticulum calcium leak that contributes to heart failure and arrhythmias.
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