Inhibition of CaMKII Phosphorylation of RyR2 prevents induction of atrial fibrillation in FKBP12.6 Knockout Mice
Rationale: Abnormal calcium release from sarcoplasmic reticulum (SR) is considered an important trigger of atrial fibrillation (AF). Whereas increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity has been proposed to contribute to SR leak and AF induction, downstream targets of CaMK...
Gespeichert in:
| Hauptverfasser: | , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2012
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| In: |
Circulation research
Year: 2012, Jahrgang: 110, Heft: 3, Pages: 465-470 |
| ISSN: | 1524-4571 |
| DOI: | 10.1161/CIRCRESAHA.111.253229 |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1161/CIRCRESAHA.111.253229 Verlag, Volltext: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.111.253229 
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| Verfasserangaben: | Na Li, Tiannan Wang, Wei Wang, Michael J. Cutler, Qiongling Wang, Niels Voigt, David S. Rosenbaum, Dobromir Dobrev, Xander H.T. Wehrens |
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| 245 | 1 | 0 | |a Inhibition of CaMKII Phosphorylation of RyR2 prevents induction of atrial fibrillation in FKBP12.6 Knockout Mice |c Na Li, Tiannan Wang, Wei Wang, Michael J. Cutler, Qiongling Wang, Niels Voigt, David S. Rosenbaum, Dobromir Dobrev, Xander H.T. Wehrens |
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| 500 | |a Originally published: December 8, 2011 | ||
| 500 | |a Gesehen am 30.10.2018 | ||
| 520 | |a Rationale: Abnormal calcium release from sarcoplasmic reticulum (SR) is considered an important trigger of atrial fibrillation (AF). Whereas increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity has been proposed to contribute to SR leak and AF induction, downstream targets of CaMKII remain controversial. Objective: To test the hypothesis that inhibition of CaMKII-phosphorylated type-2 ryanodine receptors (RyR2) prevents AF initiation in FKBP12.6-deficient (−/−) mice. Methods and Results: Mice lacking RyR2-stabilizing subunit FKBP12.6 had a higher incidence of spontaneous and pacing-induced AF compared with wild-type mice. Atrial myocytes from FKBP12.6−/− mice exhibited spontaneous Ca2+ waves (SCaWs) leading to Na+/Ca2+-exchanger activation and delayed afterdepolarizations (DADs). Mutation S2814A in RyR2, which inhibits CaMKII phosphorylation, reduced Ca2+ spark frequency, SR Ca2+ leak, and DADs in atrial myocytes from FKBP12.6−/−:S2814A mice compared with FKBP12.6−/− mice. Moreover, FKBP12.6−/−:S2814A mice exhibited a reduced susceptibility to inducible AF, whereas FKBP12.6−/−:S2808A mice were not protected from AF. Conclusions: FKBP12.6 mice exhibit AF caused by SR Ca2+ leak, Na+/Ca2+-exchanger activation, and DADs, which promote triggered activity. Genetic inhibition of RyR2-S2814 phosphorylation prevents AF induction in FKBP12.6−/− mice by suppressing SR Ca2+ leak and DADs. These results suggest suppression of RyR2-S2814 phosphorylation as a potential anti-AF therapeutic target. | ||
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