RAS差异表达在正常和肥厚左心室跨室壁复极异质性形成和改变中的作用及其机制

Transmural repolarization heterogeneity (TRH) has been widely accepted and further augmented among the mammals . However, the pathogenesis remains unknown. Many studies have corroborated the presence of autocrine renin-angiotensin system (RAS) independent of that of circulation in ventricle of mammals. Local RAS is activated more than that of circulation in heart failure. Recently fewer studies founded that angiotensin mRNA is higher in ENDO than in EPI in human ventricle. Based on the extensive effects of angiotensin II on membrane ionic currents, we speculated the important effect of angiotensin II on formation and amplification of TRH in normal and hypertrophic ventricles. The present study was designed into two parts: ①to observe the mRNA and protein changes of RAS and angiotensin receptors (ATR), and changes of ionic currents in EPI, M and ENDO of normal and hypertrophic canine ventricles induced by one—kidney and one-dip renovascular hypertension; ②by the culture of adult canine EPI, M and ENDO myocytes, to observe the above parameters in the presence or absence of angiotensin II and ATR antagonist. The purpose of our study is to prove the important effect of differential expression of RAS and ATR on formation and amplification of TRH in normal and hypertrophic ventricles. By exploring the mechamism of TRH, the present study provides an important direction to develop new drug to prevent and treat ventricular arrhythmias by attenuating the differential expression of RAS and ATR in EPI, M and ENDO myocytes in the future.

哺乳动物跨室壁离子流和复极异质性（TRH）被广泛接受，左心室肥厚(LVH)时进一步扩大，但此现象形成机制未明。近年少数研究发现跨室壁内外膜心肌肾素-血管紧张素系统（RAS）表达存在差异。心室存在自分泌的，不依赖循环的RAS，LVH时其活化程度远高于循环。AngII具有广泛的急性电生理作用，推测RAS长期作用在正常和LVH时TRH形成和改变中起着重要作用。本课题①复制犬肾血管性高血压LVH模型，从mRNA、蛋白水平观测正常和LVH跨室壁三层心肌细胞RAS各成分及AT1受体、AT2受体表达，膜片钳测定细胞膜离子流及AP；②培养犬成年心肌细胞，观察Ang II干预（复制离体心肌细胞肥厚模型）与否心肌细胞上述指标的变化；观察AT1和AT2受体拮抗剂干预的影响，旨在证明跨室壁心肌自分泌RAS的差异性表达是TRH形成和扩大的重要机制，并为未来设计新型药物防治心律失常提供理论基础。

背景:哺乳动物跨室壁离子流和复极异质性（TRH）被广泛接受，左心室肥厚(LVH)时进一步扩大，但此现象形成机制未明。近年少数研究发现跨室壁内外膜心肌肾素-血管紧张素系统（RAS）表达存在差异。心室存在自分泌的，不依赖循环的RAS，LVH时其活化程度远高于循环。AngII具有广泛的急性电生理作用，推测RAS长期作用在正常和LVH时TRH形成和改变中起着重要作用。. 内容:①复制犬肾血管性高血压LVH模型，从mRNA、蛋白水平观测正常和LVH跨室壁三层心肌细胞RAS各成分及AT1受体、AT2受体表达，膜片钳测定细胞膜离子流及AP；②培养犬成年心肌细胞，观察Ang II干预（复制离体心肌细胞肥厚模型）与否心肌细胞上述指标的变化；观察AT1和AT2受体拮抗剂干预的影响。. 重要结果：①正常犬左心室肌组织RAS相关成分中存在跨室壁差异性表达，病理性心室肥厚时这种差异性表达发生明显改变；②正常犬左心室肌存在跨室壁复极异质性（离散度），病理性肥厚时跨室壁复极离散度增大，可能是导致恶性室性心律失常的重要电生理机制；③肥厚犬左心室RAS相关成分差异性表达的改变与跨室壁复极离散度的增大相关；④AT1R阻断剂显著逆转犬肥厚左心室肌组织跨室壁复极离散度的增大，可能与减轻RAS相关成分的差异性表达相关。. 科学意义：丰富哺乳类动物跨室壁离子流和复极异质性形成机制的理论；进一步剖析 ACE 抑制剂、AT 受体拮抗剂治疗心力衰竭室性心律失常的机制；为未来设计新型药物以减轻不同层次心肌细胞 RAS 及其受体差异表达的药物提供理论和实验基础，对进一步降低肥厚心室肌室性心律失常和心脏性猝死的发生具有重要意义。