基于表观遗传修饰Nrf2/ARE通路研究萝卜硫素预防血管紧张素II引起的心肌损伤

血管紧张素II（AngII）参与多种心肌病的发生和发展，氧化应激是其主要致病因素。目前外源性抗氧化剂的临床应用失败，提示调动内源性抗氧化防御机制是防治AngII心肌损伤最为有效的手段。核因子E2相关因子 2 （Nrf2）通过与抗氧化反应元件（ARE）结合，上调多种抗氧化基因的转录，构成内源性抗氧化防御系统。前期研究发现：长期低剂量AngII刺激引起心肌损伤伴随Nrf2/ARE功能下调；Nrf2 激动剂萝卜硫素（SFN）抑制AngII引起的H9c2细胞氧化损伤，伴有乙酰化水平增高及DNA甲基转移酶下调。故推测SFN能够表观遗传修饰Nrf2/ARE通路，持续激活内源性抗氧化系统，预防AngII引起的心肌损伤。为此，我们观察SFN对AngII慢性心肌损伤的保护作用，心肌Nrf2/ARE通路及Nrf2启动子区甲基化和乙酰化的变化。为临床防治AngII相关的心肌损伤提供新的靶点和手段。

Angiotensin II (AngII) is thought to play important role in the pathogenesis of many kinds of cardiomyopathy. Oxidative stress is considered as the predominant initiator of AngII-induced cardiomyopathy. Recently the failure of large clinical trials using exogenous antioxidants for the treatment of cardiovascular disease suggests that activation of endogenous antioxidant defences is the most effective strategy. The nuclear factor-erythroid 2-related factor (Nrf2) up-regulates the transcription of multiple antioxidant genes, which compose of the endogeneous antioxidant defense via binding to the antioxidant response element (ARE). In our previous studies, we demonstrated that long time treatment of subpressor dose of AngII significantly induced the cardiac oxidative damage, accompanied with the inactivation of Nrf2/ARE. In a separate project, we found that, sulforaphane (SFN), as Nrf2 activator prevented AngII-induced oxidative damage in H9c2 cells, along with hyperacetylation and inhibition of the DNA methyltransferases expression. Based on these findings we hypothesize that epigenetic up-regulation of Nrf2/ARE pathway by sulforaphane prevents Angiotensin II induced-cardiomyopathy Nrf2 is a potential therapeutic target for the prevention of AngII-induced cardiac damage. To test our hypothesis, we observe whether SFN can prevent AngII-induced cardiac oxidative damage and dysfunction; evaluate Nrf2/ARE activation as well as methylation and acetylation in Nrf2 promoter. This project will provide scientific evidences for targeting Nrf2/ARE pathway or usage of SFN to prevent AngII-induced cardiac oxidative damage and dysfunction in clinics.