钙库超载诱导钙释放（SOICR）：房颤防治的新靶点?

The mechanisms of atrial fibrillation are very complicated and unclear. It seems that the current available strategies are not on definite target. The incidence of atrial fibrillation will keep growing in the coming decades. Based on our previous studies and most updated research data from others, we hypothesize that, the Store Overload Induced Calcium Release (SOICR), standing for the diastolic spontaneous calcium release from sarcoplasmic reticulum (SR) through the SR calcium release channel, Ryanodine receptor type II (RyR2) in the cardiac myocytes, may play an important role in the mechanisms of atrial fibrillation. This project will use the transgenic mice and aged mice, surface ECG and intracardiac eletrophysiological techniques, confocal calcium imaging on isolated atrial myocytes as well as Langendorff perfused hearts, histopathology and molecular biology methods to study the relation among SOICR, DAD triggered activities, atrial eletrophysiological properties and the susceptibility of atrial fibrillation. We will test if the RyR2_E4872Q mutated heterozygous mice with less sensitive RyR2 channel to the [Ca2+] SR could alleviate the susceptibility of atrial fibrillation on high SOICR RyR2_R4496C mice and aged mice, and how? If that is the case, we can say that SOICR could be a new target for prevention and treatment of atrial fibrillation. We will also try a new drug, (R)-(+)-Carvedilol, a SOICR inhibitor we found recently, on the susceptibility of atrial fibrillation of the above mentioned high SOICR RyR2_R4496C mice and aged mice. If it work as expected, a new drug, even leading a new category of antiarrhythmic drugs, will be available in the near future for atrial fibrillation.

房颤的发生机制纷繁复杂，现有防治措施做不到有的放矢，今后几十年房颤发病率将持续走高。综合我们前期的工作基础和同行的相关研究，我们推测钙库超载诱导钙释放（SOICR）在房颤发生机制中扮演了重要角色。本项目将应用转基因高SOICR活性小鼠和老龄小鼠、在体和离体心电生理技术，分离细胞和离体心脏激光共聚焦显微镜钙成像、组织病理和分子生物学技术等，研究基因水平RyR2_E4872Q突变抑制SOICR终末环节肌浆网钙释放通道RyR2受体蛋白的[Ca2+]SR 感受器,或药物（右旋卡维地洛：(R)-(+)-Carvedilol ）抑制SOICR，对房颤易感性、心房电生理参数、心房肌细胞SOICR发生率、细胞内主要钙离子调节蛋白和钙离子介导心肌重构的主要信号分子的表达、心房肌组织病理学改变的影响，拟证实SOICR在房颤发生中的重要作用，为房颤防治寻求新的靶点，探索SOICR抑制剂在房颤防治中的潜在价值。

房颤的发生机制纷繁复杂，随着人口老龄化及心血管疾病发生率的持续走高，房颤发病率正在快速上升。现有防治措施做不到有的放矢，我们前期的工作基础和同行的相关研究，提示钙库超载诱导钙释放（SOICR）在房颤发生机制中扮演了重要角色。本项目应用转基因高SOICR活性小鼠和老龄小鼠、在体和离体心电生理技术，细胞内钙荧光显像技术，研究发现基因水平RyR2_E4872Q突变抑制SOICR终末环节肌浆网钙释放通道RyR2受体蛋白的[Ca2 +]SR 感受器,或SOICR抑制剂（右旋卡维地洛：(R)-(+)-Carvedilol ）对心房肌细胞SOICR发生率有明显抑制作用，我们还通过RyR2_R4496C HEK细胞系筛选发现了一些心脑血管保护药物对SOICR具有抑制作用，其中部分药物被认为对房颤的防治有效，我们正在继续但尚未完成的小鼠心内电生理实验部分将进一步直接验证SOICR在房颤发生中的重要作用。SOICR可能成为房颤防治一个新的靶点，SOICR抑制剂可能成为一类新的抗心律失常药物，将可能在房颤的防治中做出贡献。