BG-12调控Nrf2通路防治糖尿病心肌病

Defective glucose metabolism causes oxidative stress that directly damages the heart, resulting in diabetic cardiomyopathy (DCM). The nuclear factor-erythroid 2-related factor (Nrf2) / antioxidant response element (ARE) is a novel defensive signaling pathway against 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. Our previous study showed that diabetes induced cardiac oxidative stress and cardiac dysfunction, and Nrf2 as a critical regulator of defense against oxidative stress and damage in diabetic heart. BG-12 is a Food and Drug Administration (FDA)-approved medicine safely used for the treatment of patients with relapsing forms of multiple sclerosis for long time. New findings also showed that BG-12 also activates Nrf2 function.. In this study, we will use Nrf2 knockout (Nrf2-KO) and cardiac-specific overexpressing Nrf2 gene (Nrf2-TG) mice to prove the direct role of Nrf2 in the prevention of diabetic cardiomyopathy (DCM) for both type I and type II diabetes. Then we will define whether BG-12 also protects from, and treat DCM via up-regulation of Nrf2, as well as how BG-12 up-regulates Nrf2 by epigenetic and non-epigenetic pathways. This project will provide the theoretic base for repurposing of BG-12 to new targets (diseases).

糖代谢异常诱发氧化应激损伤心肌，导致糖尿病心肌病（DCM）。NF-E2相关因子2（Nrf2）/抗氧化反应元件（ARE）是机体抵抗内外界氧化和化学等刺激的重要的防御性转导通路，调控多种抗氧化因子的表达抵抗氧化应激损伤。BG-12（富马酸二甲酯）是目前用于临床治疗成人多发性硬化的药物，研究表明其也能激活Nrf2上调。我们在前期研究中发现，糖尿病显著增加心肌氧化应激损伤导致DCM，激活Nrf2通路并调节其下游抗氧化基因的表达可保护心脏损伤进而预防DCM。然而，目前尚无直接证据表明Nrf2在防治DCM中的作用。在本研究中，我们拟直接应用Nrf2基因缺失或过表达转基因小鼠证实Nrf2在DCM中的作用；同时应用BG-12，观察其是否对DCM具有防治作用，以及Nrf2的作用，并从表观遗传学和非表观遗传学两方面探讨其相应机制，为BG-12临床新的适应症的开发提供理论依据。

糖代谢异常诱发氧化应激损伤心肌，导致糖尿病心肌病（DCM）。NF-E2相关因子2（N rf2）/抗氧化反应元件（ARE）是机体抵抗内外界氧化和化学等刺激的重要的防御性转导 通路，调控多种抗氧化因子的表达抵抗氧化应激损伤。BG-12（富马酸二甲酯）是目前用 于临床治疗成人多发性硬化的药物，研究表明其也能激活Nrf2上调。我们在前期研究中发 现，糖尿病显著增加心肌氧化应激损伤导致DCM，激活Nrf2通路并调节其下游抗氧化基因 的表达可保护心脏损伤进而预防DCM。在本研究中，我们应用Nrf2基因缺失或过表达转基因小鼠证实Nrf2在DCM中的作用；同时应用BG-12，观察其对DCM具有防治作用，并发现其作用依赖于Nrf2的存在。