| First Author | Sadredini M | Year | 2021 |
| Journal | Physiol Rep | Volume | 9 |
| Issue | 18 | Pages | e15030 |
| PubMed ID | 34558218 | Mgi Jnum | J:317279 |
| Mgi Id | MGI:6787938 | Doi | 10.14814/phy2.15030 |
| Citation | Sadredini M, et al. (2021) The oxidation-resistant CaMKII-MM281/282VV mutation does not prevent arrhythmias in CPVT1. Physiol Rep 9(18):e15030 |
| abstractText | Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is an inherited arrhythmogenic disorder caused by missense mutations in the cardiac ryanodine receptors (RyR2), that result in increased beta-adrenoceptor stimulation-induced diastolic Ca(2+) leak. We have previously shown that exercise training prevents arrhythmias in CPVT1, potentially by reducing the oxidation of Ca(2+) /calmodulin-dependent protein kinase type II (CaMKII). Therefore, we tested whether an oxidation-resistant form of CaMKII protects mice carrying the CPVT1-causative mutation RyR2-R2474S (RyR2-RS) against arrhythmias. Antioxidant treatment (N-acetyl-L-cysteine) reduced the frequency of beta-adrenoceptor stimulation-induced arrhythmogenic Ca(2+) waves in isolated cardiomyocytes from RyR2-RS mice. To test whether the prevention of CaMKII oxidation exerts an antiarrhythmic effect, mice expressing the oxidation-resistant CaMKII-MM281/282VV variant (MMVV) were crossed with RyR2-RS mice to create a double transgenic model (RyR2-RS/MMVV). Wild-type mice served as controls. Telemetric ECG surveillance revealed an increased incidence of ventricular tachycardia and an increased arrhythmia score in both RyR2-RS and RyR2-RS/MMVV compared to wild-type mice, both following a beta-adrenoceptor challenge (isoprenaline i.p.), and following treadmill exercise combined with a beta-adrenoceptor challenge. There were no differences in the incidence of arrhythmias between RyR2-RS and RyR2-RS/MMVV mice. Furthermore, no differences were observed in beta-adrenoceptor stimulation-induced Ca(2+) waves in RyR2-RS/MMVV compared to RyR2-RS. In conclusion, antioxidant treatment reduces beta-adrenoceptor stimulation-induced Ca(2+) waves in RyR2-RS cardiomyocytes. However, oxidation-resistant CaMKII-MM281/282VV does not protect RyR2-RS mice from beta-adrenoceptor stimulation-induced Ca(2+) waves or arrhythmias. Hence, alternative oxidation-sensitive targets need to be considered to explain the beneficial effect of antioxidant treatment on Ca(2+) waves in cardiomyocytes from RyR2-RS mice. |
