中文摘要：

本文旨在建立转基因联合抑制心脏钙/钙调素依赖性蛋白激酶II（Ca2＋/calmodulin-dependent protein kinase II,Ca MKII）及内向整流性钾电流（Ik1）小鼠模型,初步探讨该联合抑制在基础和应激状态下对小鼠心脏电生理、结构与功能重构的影响。将动物分为4组：野生组（WT）,转基因Ca MKII抑制组（AC3-I）,转基因Ik1抑制组（Kir2.1-AAA）,转基因联合抑制组（AC3-I＋Kir2.1-AAA）。记录各组动物在基础状态下及注射异丙肾上腺素后的心电图;同时分别对各组动物进行心脏超声检查,以了解心脏重构情况;在酶解法分离单个左室心肌细胞后,采用全细胞膜片钳法记录心肌细胞Ik1和瞬间外向钾电流（Ito）。实验结果显示：在基础状态下,心电图显示各组动物之间的心率、PR间期和QRS间期均无显著差别;注射异丙基肾上腺素后,上述心电图指标和小鼠发生室性心律失常的情况在各组间也无显著差别;4组小鼠间M型（Motion-mode）和二维超声检测的各项指标无显著差异;全细胞膜片钳实验结果表明,AC3-I组动物心肌细胞的Ik1电流密度最大（P〈0.01）,WT组的次之（P〈0.01）,其他两组较WT组显著降低（P〈0.01）;同时,AC3-I组Ito电流密度显著高于其他三组（P〈0.01）,而其他三组间无明显差异。上述结果提示：转基因联合抑制Ca MKII和Ik1可使Ca MKII抑制的小鼠Ik1下调,在基础状态下不影响心脏的结构和功能变化,在注射异丙基肾上腺素后心律失常的发生亦无明显差别。本结果为进一步探讨联合抑制Ca MKII与Ik1在各种心脏疾病状态下能否更有效地拮抗心肌的不利重构打下了基础。

英文摘要：

This study was aimed to establish an experimental mouse model of combined transgenic inhibition of both multifunctional Ca2＋/calmodulin-dependent protein kinase II（Ca MKII） and inward rectifier potassium current（Ik1）, and to observe whether the specific inhibition of both Ca MKII and Ik1 can bring about any effects on cardiac remodeling. Mice were divided into 4 groups： wild type（WT）, Ca MKII inhibited（AC3-I）, Ik1 inhibited（Kir2.1-AAA） and combined inhibition of both Ca MKII and Ik1（AC3-I＋Kir2.1-AAA）. Mice in each group received electrocardiogram（ECG） and echocardiography examination. ECG in the condition of isoproterenol（ISO） injection was also checked. The whole cell patch clamp technique was used to measure Ik1 and the transient outward potassium current（Ito） from enzymatically isolated myocytes of left ventricle. In the condition of basal status, no significant changes of heart rate, PR interval and QRS interval were observed. No mouse showed ventricular arrhythmias in all of the 4 groups. After ISO injection, each group presented no significant ventricular arrhythmias either. The indexes measured by M-mode（motion-mode） and two-dimensional echocardiography had no significant differences among the four groups. Ik1 in AC3-I group was significantly higher than those in other three groups（P〈0.01） because of the results brought about by Ca MKII inhibition. Among the latter three groups, both Kir2.1-AAA group and AC3-I＋Kir2.1-AAA group had a significant reduced Ik1 compared with that of WT group, which was due to the Ik1 inhibition（P〈0.01）. Ito in AC3-I group was higher than that of the other three groups（P〈0.01）, but there were no significant differences in Ito among WT, Kir2.1-AAA and AC3-I＋Kir2.1-AAA groups. Thus, combined transgenic myocardial Ca MKII and Ik1 inhibition eliminated the up-regulation of Ik1 in Ca MKII inhibited mice, and had no effects on cardiac remodeling including heart structure and function as well as arrhythmias at the basi