Department of Cardiology and Pneumology/Heart Center, Georg-August-University Göttingen, Robert-Koch-Strasse 40, Göttingen, Germany.
Circ Res. 2010 Apr 2;106(6):1134-44. doi: 10.1161/CIRCRESAHA.109.203836. Epub 2010 Jan 7.
Although research suggests that diastolic Ca(2+) levels might be increased in atrial fibrillation (AF), this hypothesis has never been tested. Diastolic Ca(2+) leak from the sarcoplasmic reticulum (SR) might increase diastolic Ca(2+) levels and play a role in triggering or maintaining AF by transient inward currents through Na(+)/Ca(2+) exchange. In ventricular myocardium, ryanodine receptor type 2 (RyR2) phosphorylation by Ca(2+)/calmodulin-dependent protein kinase (CaMK)II is emerging as an important mechanism for SR Ca(2+) leak.
We tested the hypothesis that CaMKII-dependent diastolic SR Ca(2+) leak and elevated diastolic Ca(2+) levels occurs in atrial myocardium of patients with AF.
We used isolated human right atrial myocytes from patients with AF versus sinus rhythm and found CaMKII expression to be increased by 40+/-14% (P<0.05), as well as CaMKII phosphorylation by 33+/-12% (P<0.05). This was accompanied by a significantly increased RyR2 phosphorylation at the CaMKII site (Ser2814) by 110+/-53%. Furthermore, cytosolic Ca(2+) levels were elevated during diastole (229+/-20 versus 164+/-8 nmol/L, P<0.05). Most likely, this resulted from an increased SR Ca(2+) leak in AF (P<0.05), which was not attributable to higher SR Ca(2+) load. Tetracaine experiments confirmed that SR Ca(2+) leak through RyR2 leads to the elevated diastolic Ca(2+) level. CaMKII inhibition normalized SR Ca(2+) leak and cytosolic Ca(2+) levels without changes in L-type Ca(2+) current.
Increased CaMKII-dependent phosphorylation of RyR2 leads to increased SR Ca(2+) leak in human AF, causing elevated cytosolic Ca(2+) levels, thereby providing a potential arrhythmogenic substrate that could trigger or maintain AF.
尽管有研究表明，在心房颤动（AF）中舒张期 Ca(2+) 水平可能会升高，但这一假说从未得到过验证。肌浆网（SR）中的舒张期 Ca(2+) 渗漏可能会通过 Na(+)/Ca(2+) 交换的内向电流增加舒张期 Ca(2+) 水平，并在触发或维持 AF 中发挥作用。在心室心肌中，Ca(2+)/钙调蛋白依赖性蛋白激酶（CaMK）II 对肌浆网型 2 型受体（RyR2）的磷酸化作用正成为 SR Ca(2+) 渗漏的一个重要机制。
我们检验了这样一个假说，即在 AF 患者的心房心肌中，CaMKII 依赖性舒张期 SR Ca(2+) 渗漏和升高的舒张期 Ca(2+) 水平是否会发生。
我们使用了来自 AF 患者与窦性节律患者的分离的人右心房心肌细胞，发现 CaMKII 的表达增加了 40+/-14%（P<0.05），同时 CaMKII 磷酸化增加了 33+/-12%（P<0.05）。这伴随着 RyR2 在 CaMKII 位点（Ser2814）的磷酸化显著增加了 110+/-53%。此外，在舒张期细胞浆内 Ca(2+) 水平升高（229+/-20 比 164+/-8 nmol/L，P<0.05）。很可能是由于 AF 时 SR Ca(2+) 渗漏增加（P<0.05）所致，而不是由于 SR Ca(2+) 负荷增加所致。四卡因实验证实，通过 RyR2 的 SR Ca(2+) 渗漏导致舒张期 Ca(2+) 水平升高。CaMKII 抑制使 SR Ca(2+) 渗漏和细胞浆 Ca(2+) 水平恢复正常，而不会改变 L 型 Ca(2+) 电流。
RyR2 的 CaMKII 依赖性磷酸化增加导致人 AF 中 SR Ca(2+) 渗漏增加，导致细胞浆 Ca(2+) 水平升高，从而提供了一种潜在的心律失常基质，可能触发或维持 AF。
