Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany.
J Am Coll Cardiol. 2011 Jan 25;57(4):469-79. doi: 10.1016/j.jacc.2010.08.639.
We investigated whether increased Ca(2+)/calmodulin-dependent kinase II (CaMKII) activity aggravates defective excitation-contraction coupling and proarrhythmic activity in mice expressing R4496C mutated cardiac ryanodine receptors (RyR2).
RyR2 dysfunction is associated with arrhythmic events in inherited and acquired cardiac disease.
CaMKIIδc transgenic mice were crossbred with RyR2(R4496C+/-) knock-in mice.
Heart weight-to-body weight ratio in CaMKIIδc/RyR2(R4496C) and CaMKIIδc mice was similarly increased approximately 3-fold versus wild-type mice (p < 0.05). Echocardiographic data showed comparable cardiac dilation and impaired contractility in CaMKIIδc/RyR2(R4496C) and CaMKIIδc mice. Sarcoplasmic reticulum Ca(2+) content in isolated myocytes was decreased to a similar extent in CaMKIIδc/RyR2(R4496C) and CaMKIIδc mice. However, relaxation parameters and Ca(2+) decay at 1 Hz were prolonged significantly in CaMKIIδc mice versus CaMKIIδc/RyR2(R4496C) mice. Sarcoplasmic reticulum Ca(2+) spark frequency and characteristics indicated increased sarcoplasmic reticulum Ca(2+) leak in CaMKIIδc/RyR2(R4496C) versus CaMKIIδc myocytes (p < 0.05), most likely because of increased RyR2 phosphorylation. Delayed afterdepolarizations were significantly more frequent with increased amplitudes in CaMKIIδc/RyR2(R4496C) versus CaMKIIδc mice. Increased arrhythmias in vivo (67% vs. 25%; p < 0.05) may explain the increased mortality in CaMKIIδc/RyR2(R4496C) mice, which died prematurely with only 30% alive (vs. 60% for CaMKIIδc, p < 0.05) after 14 weeks.
CaMKIIδc overexpression in RyR2(R4496C+/-) knock-in mice increases the propensity toward triggered arrhythmias, which may impair survival. CaMKII contributes to further destabilization of a mutated RyR2 receptor.
我们研究了钙/钙调蛋白依赖性激酶 II（CaMKII）活性增加是否会加重表达 R4496C 突变型心肌兰尼碱受体（RyR2）的小鼠中缺陷的兴奋-收缩偶联和致心律失常活性。
RyR2 功能障碍与遗传性和获得性心脏病中的心律失常事件有关。
将 CaMKIIδc 转基因小鼠与 RyR2（R4496C+/-）基因敲入小鼠杂交。
与野生型小鼠相比，CaMKIIδc/RyR2（R4496C）和 CaMKIIδc 小鼠的心脏重量/体重比分别增加约 3 倍（p<0.05）。超声心动图数据显示，CaMKIIδc/RyR2（R4496C）和 CaMKIIδc 小鼠的心脏扩张和收缩功能受损程度相似。分离的肌细胞中肌浆网 Ca（2+）含量在 CaMKIIδc/RyR2（R4496C）和 CaMKIIδc 小鼠中均显著降低。然而，与 CaMKIIδc/RyR2（R4496C）小鼠相比，CaMKIIδc 小鼠的舒张参数和 1 Hz 时的 Ca（2+）衰减明显延长。与 CaMKIIδc 肌细胞相比，CaMKIIδc/RyR2（R4496C）肌细胞的肌浆网 Ca（2+）火花频率和特征表明肌浆网 Ca（2+）渗漏增加（p<0.05），这很可能是由于 RyR2 磷酸化增加所致。延迟后除极的幅度和频率在 CaMKIIδc/RyR2（R4496C）小鼠中均明显高于 CaMKIIδc 小鼠。与 CaMKIIδc 小鼠（25%）相比，CaMKIIδc/RyR2（R4496C）小鼠体内心律失常的发生率显著增加（67%；p<0.05），这可能解释了 CaMKIIδc/RyR2（R4496C）小鼠的死亡率增加，这些小鼠在 14 周后过早死亡，只有 30%存活（而 CaMKIIδc 小鼠为 60%；p<0.05）。
在 RyR2（R4496C+/-）基因敲入小鼠中过表达 CaMKIIδc 会增加触发心律失常的倾向，这可能会损害生存能力。CaMKII 有助于进一步使突变型 RyR2 受体失稳。
