The role of RyR2 oxidation in the blunted frequency-dependent facilitation of Ca(2+) transient amplitude in rabbit failing myocytes Journal Article

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Authors: Bovo, E; Mazurek, S. R.; Zima, A. V.
Article Title: The role of RyR2 oxidation in the blunted frequency-dependent facilitation of Ca(2+) transient amplitude in rabbit failing myocytes
Abstract: Defective Ca(2+) regulation plays a key role in the blunted force-frequency response in heart failure (HF). Since HF is commonly associated with oxidative stress, we studied whether oxidation of ryanodine receptor (RyR2) contributes to this defect. In control ventricular myocytes, oxidative stress induced formation of disulfide bonds between RyR2 subunits: intersubunit cross-linking (XL). Western blot analysis and Ca(2+) imaging revealed a strong positive correlation between RyR2 XL and sarcoplasmic reticulum (SR) Ca(2+) leak. These results illustrate that RyR2 XL can be used as a sensitive indicator of RyR2 dysfunction during oxidative stress. HF myocytes were in a state of oxidative stress since they exhibited an increase in reactive oxygen species (ROS) level, a decrease in ROS defense and an overall protein oxidation. These myocytes were also characterized by RyR2 XL and increased SR Ca(2+) leak. Moreover, the frequency-dependent increase of Ca(2+) transient amplitude was suppressed due to the inability of the SR to maintain Ca(2+) load at high pacing rates. Because SR Ca(2+) load is determined by the balance between SR Ca(2+) uptake and leak, the blunted frequency-dependent inotropy in HF can be mediated by ROS-induced SR Ca(2+) leak. Preventing RyR2 XL in HF myocytes decreased SR Ca(2+) leak and increased Ca(2+) transients at high pacing rate. We also studied whether RyR2 oxidation alone can cause the blunted frequency-dependent facilitation of Ca(2+) transient amplitude in control myocytes. When RyR2 XL was induced in control myocytes to a similar level seen in HF, an increase of Ca(2+) transient amplitude at high pacing rate was significantly suppressed. These results suggest that SR Ca(2+) leak induced by RyR2 oxidation can play an important role in the blunted frequency-dependent inotropy of HF.
Journal Title: Pflugers Archiv : European journal of physiology
ISSN: 1432-2013; 0031-6768
Publisher: Unknown  
Journal Place: Germany
Date Published: 2018
Language: eng
DOI/URL:

10.1007/s00424-018-2122-3
Notes: LR: 20180307; GR: R01 HL130231/HL/NHLBI NIH HHS/United States; GR: HL130231/Foundation for the National Institutes of Health; JID: 0154720; OTO: NOTNLM; 2018/01/04 00:00 [received]; 2018/02/13 00:00 [accepted]; 2018/01/31 00:00 [revised]; 2018/03/04 06:00 [entrez]; 2018/03/04 06:00 [pubmed]; 2018/03/04 06:00 [medline]; aheadofprint