| First Author | Sadredini M | Year | 2021 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 321 |
| Issue | 2 | Pages | H446-H460 |
| PubMed ID | 34270372 | Mgi Jnum | J:310401 |
| Mgi Id | MGI:6762489 | Doi | 10.1152/ajpheart.00011.2021 |
| Citation | Sadredini M, et al. (2021) CaMKII inhibition has dual effects on spontaneous Ca(2+) release and Ca(2+) alternans in ventricular cardiomyocytes from mice with a gain-of-function RyR2 mutation. Am J Physiol Heart Circ Physiol 321(2):H446-H460 |
| abstractText | In conditions with abnormally increased activity of the cardiac ryanodine receptor (RyR2), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) can contribute to a further destabilization of RyR2 that results in triggered arrhythmias. Therefore, inhibition of CaMKII in such conditions has been suggested as a strategy to suppress RyR2 activity and arrhythmias. However, suppression of RyR2 activity can lead to the development of arrhythmogenic Ca(2+) alternans. The aim of this study was to test whether the suppression of RyR2 activity caused by inhibition of CaMKII increases propensity for Ca(2+) alternans. We studied spontaneous Ca(2+) release events and Ca(2+) alternans in isolated left ventricular cardiomyocytes from mice carrying the gain-of-function RyR2 mutation RyR2-R2474S and from wild-type mice. CaMKII inhibition by KN-93 effectively decreased the frequency of spontaneous Ca(2+) release events in RyR2-R2474S cardiomyocytes exposed to the beta-adrenoceptor agonist isoprenaline. However, KN-93-treated RyR2-R2474S cardiomyocytes also showed increased propensity for Ca(2+) alternans and increased Ca(2+) alternans ratio compared with both an inactive analog of KN-93 and with vehicle-treated controls. This increased propensity for Ca(2+) alternans was explained by prolongation of Ca(2+) release refractoriness. Importantly, the increased propensity for Ca(2+) alternans in KN-93-treated RyR2-R2474S cardiomyocytes did not surpass that of wild type. In conclusion, inhibition of CaMKII efficiently reduces spontaneous Ca(2+) release but promotes Ca(2+) alternans in RyR2-R2474S cardiomyocytes with a gain-of-function RyR2 mutation. The dominant effect in RyR2-R2474S is to reduce spontaneous Ca(2+) release, which supports this intervention as a therapeutic strategy in this specific condition. However, future studies on CaMKII inhibition in conditions with increased propensity for Ca(2+) alternans should include investigation of both phenomena.NEW & NOTEWORTHY Genetically increased RyR2 activity promotes arrhythmogenic Ca(2+) release. Inhibition of CaMKII suppresses RyR2 activity and arrhythmogenic Ca(2+) release. Suppression of RyR2 activity prolongs refractoriness of Ca(2+) release. Prolonged refractoriness of Ca(2+) release leads to arrhythmogenic Ca(2+) alternans. CaMKII inhibition promotes Ca(2+) alternans by prolonging Ca(2+) release refractoriness. |
