| First Author | Sufu-Shimizu Y | Year | 2020 |
| Journal | Biochem Biophys Res Commun | Volume | 524 |
| Issue | 2 | Pages | 431-438 |
| PubMed ID | 32007269 | Mgi Jnum | J:297403 |
| Mgi Id | MGI:6472081 | Doi | 10.1016/j.bbrc.2020.01.107 |
| Citation | Sufu-Shimizu Y, et al. (2020) Stabilizing cardiac ryanodine receptor prevents the development of cardiac dysfunction and lethal arrhythmia in Ca(2+)/calmodulin-dependent protein kinase IIdeltac transgenic mice. Biochem Biophys Res Commun 524(2):431-438 |
| abstractText | AIMS: Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) has been shown to induce aberrant Ca(2+) release from the cardiac ryanodine receptor (RyR2) in various diseased hearts. However, the precise pathogenic mechanism remains to be elucidated. Here, we investigated the effect of dantrolene (DAN): a RyR2 stabilizer on local Ca(2+) release, cardiac function, and lethal arrhythmia in CaMKIIdeltac transgenic (TG) mice. METHODS AND RESULTS: The TG mice showed an increase in left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) with a reduction in LV fractional shortening (LVFS). The phosphorylation levels of Ser2814 in RyR2 and Thr287 in CaMKII increased in TG mice. In TG cardiomyocytes, peak cell shortening (CS) decreased, and the frequency of spontaneous Ca(2+) transients (sCaTs) increased. Endogenous RyR2-associated calmodulin (CaM) markedly decreased in TG cardiomyocytes. After chronic DAN treatment for 1 month, LVESD (but not LVEDD) decreased with an increase in LVFS. In the chronic DAN-treated cardiomyocytes, CS increased, sCaTs decreased, and the endogenous CaM binding to RyR2 normally restored. The phosphorylation levels of Ser2814 in RyR2 and Thr287 in CaMKII remained elevated even after DAN treatment. Moreover, in TG mice, chronic DAN treatment prevented sustained ventricular tachycardia induced by epinephrine. CONCLUSIONS: Defective association of CaM with RyR2 is most likely to be involved in the pathogenesis of CaMKII-mediated cardiac dysfunction and lethal arrhythmia. |
