高血糖时缺血后处理心肌保护作用的抵抗产生“代谢记忆”效应的关键：感觉神经TRPV1受体

项目名称： 高血糖时缺血后处理心肌保护作用的抵抗产生“代谢记忆”效应的关键：感觉神经TRPV1受体

项目编号： No.81200080

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 宋俊贤

作者单位： 北京大学

项目金额： 24万元

中文摘要： 申请人前期工作显示糖尿病心脏对缺血后处理的心肌保护作用存在抵抗，其机制与心脏感觉神经末梢上的心肌缺血感受器-TRPV1受体受损有关。但最新研究表明糖尿病发生较长时间后尽管使血糖恢复正常，缺血后处理心肌保护作用的抵抗仍然存在，这提示该抵抗在高血糖时可能存在"代谢记忆"效应。本项目采用公认的高血糖"代谢记忆"动物和细胞模型，观察缺血后处理在在体和离体心肌缺血再灌注中对缺血再灌注损伤包括心肌细胞死亡（坏死、凋亡和自噬）、心功能、无再流和再灌注心律失常的影响，以及TRPV1受体表达、分布、激活和心肌保护功能的变化，明确缺血后处理心肌保护作用抵抗和TRPV1受体受损在高血糖时是否存在"代谢记忆"；并进一步应用药物和基因转染方法纠正糖尿病心脏感觉神经病变，观察上述两种"代谢记忆"的改变及相互关系，为高血糖时缺血后处理心肌保护抵抗产生"代谢记忆"的机制提供解释，并为消除这些不良"代谢记忆"提供干预靶点。

中文关键词： TRPV1受体；缺血后处理；代谢记忆；非编码RNA；肠道菌群

英文摘要： Our previous studies found that diabetic hearts were resistant to cardioprotection by ischemic postconditioning (IPostC), and the underlying mechanism was related to the impairment of TRPV1 on cardiac sensory nerves in the presence of hyperglycemia. Recently, a study reported that the resistance to cardioprotection by IPostC in streptozotocin (STZ)-induced type 1 diabetic mice was reversed by restoration of normoglycemia with insulin treatment. However, another evidence has shown that the resistance to cardioprotection by IPostC was not restored by normoglycemia using insulin in type 1 diabetic rats induced by STZ injection. Discrepancy between these two studies may be due to hyperglycemic times, as the hyperglycemic time increases, the inhibited protective function of IPostC by diabetes may become irreversible. These results suggest that "metabolic memory" occurs in the resistance to cardioprotection by IPostC during hyperglycemia. However, little is known about whether hyperglycemia can result in "metabolic memory" in the resistance to IPostC-induced cardioprotection, and the potential mechanisms responsible for this "metabolic memory". In order to provide definite evidence that the phenomenon of "metabolic memory" also occurs in the resistance to cardioprotection by IPostC and the impairment of TRPV1 on senso

英文关键词： TRPV1 receptor；ischemic postconditioning；metabolic memory；non-coding RNA；gut microbiota