调控Nrf2信号通路预防糖尿病心肌病的机制

Defective glucose metabolism causes oxidative stress that directly damages the heart, resulting in diabetic cardiomyopathy. The nuclear factor-erythroid 2 -related factor (Nrf2) /ARE (antioxidant response element) is a novel defensive signaling pathway involved in oxidative and chemical stress of cells. Nrf2 is a transcription factor that plays a crucial role in the cellular redox homeostasis through up-regulation of several antioxidants. Resveratrol is effective free radical scavenger, but the mechanism of antioxidative protection is still unknown. Our previous study showed that Nrf2 as a critical regulator of defense against oxidative stress and damage in diabetic heart, by showing that cardiomyocytes or the heart of Nrf2 null mice are highly susceptible to oxidative damage caused by high level of glucose (HG) in vitro or hyperglycemia in vivo. Resveratrol can protect heart from diabetic damage by regulating protein kinase (AKT2). Therefore, the specific hypothesis of this project is that Resveratrol can up-regulate cadiac Nrf2 expression and function in vivo via enhancing multiple antioxidant pathways to provide a significant cardiac protection from diabetes-induced oxidative damage, remodeling and dysfunction. We will use different knockout mice, set up type Ⅰand type Ⅱ diabetic models, analyze the pivotal role of Nrf2 in protection of diabetic cardiomyopathy, identify the mechanism of Resveratrol protection of diabetic cardiomyopathy. This project will provide rational for Resveratrol to be used in clinics, and provide the potential of induction of Nrf2 in protection of diabetic cardiomyopathy.

糖代谢异常诱发氧化应激损害心肌，导致糖尿病性心肌病。NF-E2相关因子（Nrf2）/抗氧化反应元件（ARE）是新近发现的机体抵抗内外界氧化应激和化学等刺激的防御性转导通路，Nrf2可以调控多种抗氧化基因表达抵抗氧化应激。白藜芦醇作为高效自由基清除剂，其抗氧化作用机制尚不清楚。我们前期研究发现，与Nrf2野生鼠相比，高糖可诱导Nrf2基因敲除鼠体外培养心肌细胞ROS生成增多，糖尿病鼠的心肌损伤加重。我们还发现，白藜芦醇能通过调控蛋白激酶（AKT2）信号通路发挥糖尿病心肌的保护作用。因此，我们推测，白藜芦醇可能通过上调心肌Nrf2的表达，上调多种抗氧化基因，而非单一抗氧化基因发挥糖尿病心肌的保护作用。本课题拟采用不同基因敲除鼠鼠，通过Ⅰ型和Ⅱ型糖尿病动物模型，层层分析Nrf2在糖尿病心肌病中的作用，明确白藜芦醇发挥糖尿病心肌保护的作用机制，为通过诱导Nrf2防治糖尿病心肌病提供理论依据。

糖尿病心肌病（Diabetic Cardiomyopathy, DCM）是糖尿病患者严重的血管并发症之一。糖尿病血管并发症的发病机制比较复杂，多种致病因素可能通过不同的机制引发和加剧糖尿病心肌病、糖尿病大血管病变及糖尿病其它并发症，但这些致病作用都与炎症及氧化应激密切相关。NF-E2相关因子（Nrf2）/抗氧化反应元件（ARE）是机体抵抗内外界氧化应激和化学等刺激的防御性转导通路，Nrf2可以调控多种抗氧化基因表达抵抗氧化应激。因此，选择合适的抗氧化剂，上调Nrf2的表达，进而上调多种抗氧化基因，或调控不同信号通路抑制炎症因子发挥对糖尿病心肌及血管的保护作用具有重要的意义。白藜芦醇、锌、花椰菜等作为安全、可以作为有效的诱导剂诱导体内金属硫蛋白的表达，上调Nrf2的表达进而提高机体的抗氧化能力，在防治糖尿病心血管并发症方面有广阔的应用前景。本课题采用不同基因敲除鼠，通过Ⅰ型和Ⅱ型糖尿病动物模型，层层分析Nrf2在糖尿病心肌病及糖尿病大血管中的作用，明确抗氧化剂的保护机制，为通过诱导Nrf2，或抑制炎症防治糖尿病并发症提供理论依据，也为临床应用锌、白藜芦醇等作为有效抗氧化剂提供理论基础。