Nrf2激动剂Dh404预防糖尿病心肌胰岛素抵抗和糖尿病心肌病的机制

Diabetic cardiomyopathy is one of major diabetic complications. Oxidative stress is the predominant pathogenesis of diabetic cardiac insulin resistance and diabetic cardiomyopathy. The nuclear factor- erythroid 2-related factor (Nrf2) is a transcription factor that plays a crucial role in the cellular redox homeostasis through up-regulation of several antioxidants and detoxifying enzymes. In our preliminary studies, we have found that the expression and function of Nrf2 (nuclear translocation) were significantly down-regulated in cardiac tissue in late-stage diabetic patients and experimental animals, which was accompanies by serious cardiac oxidative damage; while a novel Nrf2 activator Dh404 can up-regulate the function of Nrf2 and its downstream antioxidant genes to prevent cardiac oxidative damage and protect cardiac insulin signaling in a diabetic animal model. Based on these findings, we hypothesize that Nrf2 is a potential therapeutic target for the prevention of diabetic cardiac insulin resistance and diabetic cardiomyopathy. Utilization of Nrf2 activator Dh404 up-regulation of the function of Nrf2 and its downstream multiple antioxidants can protect the heart from diabetic oxidative damage, cardiac insulin resistance and consequently prevent diabetic cardiomyopathy. To test our hypothesis, three specific aims are proposed: 1) To define whether Nrf2 activator Dh404 can prevent diabetic cardiac insulin resistance and diabetic cardiomyopathy in streptozotocin-induced and spontaneous OVE26 type 1 diabetes; 2) To define the pivotal role of Nrf2 in Nrf2 activator Dh404 protection of heart from diabetes; 3) To define the mechanism that Dh404 up-regulation of Nrf2 to prevent cardiac insulin resistance and cardiomyopathy in diabetes. The objective of this project is to verify that targeting to up-regulation of Nrf2 function in vivo by its activator Dh404 can provide a significant protection from diabetes-induced cardiac oxidative damage, insulin resistance, remodeling and dysfunction, which will provide strong scientific evidences for targeting Nrf2 to prevent diabetic complication in clinics.

氧化应激是导致糖尿病心肌胰岛素抵抗和糖尿病心肌病的关键因素。核因子E2相关因子2 (Nrf2)在机体氧化－还原体系调控中起着重要的作用。预实验发现：晚期糖尿病病人和实验动物心肌Nrf2表达显著下调、心肌损伤加重；利用Nrf2激活剂Dh404诱导Nrf2上调能有效预防糖尿病动物心肌氧化损伤、保护心肌胰岛素信号。课题组据此提出科学假设：Nrf2是预防糖尿病心肌胰岛素抵抗和糖尿病心肌病的有效靶点，采用Nrf2激动剂Dh404上调Nrf2的功能、增强其下游多种抗氧化信号能有效预防心肌氧化损伤和胰岛素抵抗，从而预防糖尿病心肌病。本课题的主要目标是考察以Nrf2为靶点、利用Nrf2激动剂Dh404预防糖尿病心肌胰岛素抵抗和心肌病的可行性和有效性，同时以多种转基因动物模型为研究手段，解析Dh404上调Nrf2预防糖尿病心肌胰岛素抵抗和心肌病的分子机制，为临床以Nrf2为靶点预防糖尿病心肌病提供科学依据。

本课题的总体目标是系统考察以Nrf2为靶点防治糖尿病心肌病的有效性，并利用小鼠NRF2-TG和NRF2-KO模型系统以NRF2为靶点预防糖尿病心肌胰岛素抵抗和糖尿病心肌病的分子细胞机制，为将来开发以NRF2为靶点、治疗糖尿病心血管并发症的药物提供科学依据。课题组紧紧围绕既定研究目标，密切关注国际、国内研究热点，积极跟踪国际前沿，创造性的完成了如下研究工作：1）证实NRF2是预防1型、2型和ANG II诱导的心肌胰岛素抵抗和/或心肌损伤的有效靶点；2）利用NRF2-TG和NRF2-KO转基因动物模型系统NRF2在预防糖尿病心肌胰岛素抵抗和心肌损伤中起关键作用；3）证实NRF2和/或MT等抗氧化基因主要通过维持心肌AKT、特别是AKT2的功能，从而保护心肌的抗氧化应激和糖脂代谢信号系统，维持心肌细胞正常的抗氧化和能量代谢功能，从而预防糖尿病心肌病的发生和发展。.通过本课题的实施，正式发表SCI研究论文15篇，累计SCI影响因子63.42，另外还有多篇论文正在投递中；课题组主要成员多次参加国际会议，发表国际会议论文摘要18篇、并做大会发言6次；部分研究成果获得浙江省科技进步一等奖、中华医学科技奖三等奖和教育部自然科学一等奖各1项；主持人分别入选浙江省高等学校“钱江学者”特聘教授、浙江省“151”第一层次人才支持计划和温州市“551”第一层次人才支持计划；以本课题为载体，培养青年教师2名、联合培养博士研究生1名，博士后2名，硕士研究生4名。