中文摘要：

目的以双特异性酪氨酸磷酸化调节激酶1A（Dyrk1A）-可变剪接因子（ASF）-钙／钙调素依赖蛋白激酶Ⅱδ（CaMKⅡδ）信号通路为研究对象，探讨美托洛尔预防腹主动脉缩窄大鼠心肌肥厚的机制。方法健康、雄性SpragueDawley（SD）大鼠30只，采用随机数字表法分为假手术组、腹主动脉缩窄组（模型组）和美托洛尔干预组（美托洛尔组，在腹主动脉缩窄基础上每日予美托洛尔干预）3组，每组10只。检测大鼠血压及心肌肥厚程度，免疫印迹法检测大鼠心肌Dyrk1A、ASF蛋白表达水平，RT—PCR法检测大鼠心肌CaMKⅡδ可变剪接。结果术后4周，模型组和美托洛尔组大鼠动脉收缩压（SBP）、舒张压（DBP）均显著高于假手术组（P均〈0．05），美托洛尔组与模型组比较差异无统计学意义。模型组大鼠左心室质量／体质量（LVW／BW）值较假手术组高36％（P〈0．05），美托洛尔组则显著低于模型组（P〈0．05）。模型组大鼠心肌细胞面积为假手术组的2．14倍（P〈0．05），美托洛尔组则仅为模型组的58．2％（P〈0．05）。模型组大鼠左心室心肌Dyrk1A蛋白表达水平为0．92±0．13，明显高于假手术组的0．33±0．05（P〈0．05），美托洛尔组为0．36±0．09，显著低于模型组（P〈0．05）。模型组大鼠左心室心肌ASF蛋白表达水平为0．133±0．018，显著低于假手术组的0．322±0．012（P〈0．05），美托洛尔组为0．301±0．014，显著高于模型组（P〈0．05）。模型组大鼠左心室心肌CaMKⅡδA、B亚型mRNA表达水平均显著高于假手术组（P均〈0．05），CaMKII6C亚型则显著低于假手术组（P〈0．05）。美托洛尔组大鼠左心室心肌CaMKⅡδA、B亚型mRNA表达则均显著低于模型组（P均〈0．05），CaMKⅡδC亚型则显著高于模型组（P〈0．05）。结论Dyrk1A经ASF调控CaMKⅡδ可变剪接参与了腹主动脉缩窄大鼠心肌肥厚的发?

英文摘要：

Objective Previous study showed that the signaling pathway of dual-specificity tyrosine- phosphorylated and regulated kinase 1 A （Dyrk1A）-alternative splicing factor （ASF）- alternative splicing of Ca^2 ＋/calmodulin-dependent protein kinase Ⅱδ（ CaMK Ⅱδ） is related to myocardial hypertrophy. The aim of present study was to determine the effect and related mechamism of metoprolol on pressure overload induced myocardial hypertrophy. Methods Pressure overload-induced hypertension was induced by eoarctation of suprarenal abdominal aorta in rats. Rats were randomly divided into sham-operated control,hypertension and hypertension plus metoprolol （30 mg · kg^-1 · d^-1） groups （n = 10 each）. Blood pressure, the left ventricular weight to body weight ratio and cardiomyocytes area were measured, the protein expression of Dyrkl A and ASF were determined by Western blot and mRNA expression of alternative splicing of CaMK Ⅱδ was detected by RT-PCR. Results Four weeks after coarctation, cardiac hypertrophy was evidenced in rats of hypertensive group, and the protein expression of Dyrkl A was significantly upregulated, while the expression of ASF was significantly downregulated, the mRNA expression of CaMK Ⅱδ A and B were significantly upregulated and mRNA expression of CaMK ⅡδC was significantly downregulated compared to those in sham-operated control rats （ all P 〈 0. 05 ）. Treatment with metoprolol effectively attenuated cardiac hypertrophy and reversed pressure overload induced changes on DyrklA and ASF, and alternative splicing of CaMK Ⅱδ （ all P 〈 0.05 ）. Conclusion Metoprolol attenuates pressure overload- induced cardiac hypertrophy possibly through modulating Drykl A-ASF-CaMK Ⅱδsignaling pathways.