Nrf2基因甲基化在氧化应激诱导的“发育程序化”高血压中的作用及调控机制

Hypertension is identified as a ‘developmental programming’ disease. Oxidative stress is one of its important initial factors. We have found that the long-term antihypertensive effect of the early antioxidant treatment on the offspring rats of spontaneously hypertensive rats (SHR) was associated with a persistent reduction in methylation of Nrf2 promoter in resistance vessel. It is verified that the downregulated Nrf2 expression and activity is the molecular basis of hypertension-related resistance vessel remodeling induced by oxidative stress. It was indicated in our previous study that H3K9me3-UHRF1-DNMT1 pathway was likely to be involved in methylation maintenance. As a result, it is reasonable to hypothesize that oxidative stress in early development maintains the methylation of Nrf2 promoter through H3K9me3-UHRF1-DNMT1 pathway, leading to a decrease in Nrf2 expression. Consequently, resistance vessel is remodeled, and blood pressure is elevated. Accordingly, we plan to elucidate the effect of DNA methylation on Nrf2 expression by the method of methylation modification or methylation inhibition in Nrf2 promoter and the offspring rats of SHR as well as vascular smooth muscle cell. With the emphasis, we will clarify that H3K9me3-UHRF1-DNMT1 is the regulatory mechanism of Nrf2 methylation inheritability by the experiments of functional gain and loss of these molecules in vivo and vitro. This project is expected to provide a new insight into the epigenetic mechanism of the ‘programming of hypertension’.

高血压是“发育程序化”疾病，氧化应激是一种重要的始动因素。我们发现早期抗氧化干预自发性高血压大鼠（SHR）子鼠产生的长期降压效应与阻力血管Nrf2启动子DNA甲基化持续降低有关。但Nrf2基因甲基化的作用和可遗传的机制不明。已知Nrf2表达和活性下调是氧化应激诱导高血压阻力血管重塑的分子基础。我们前期工作也显示H3K9me3-UHRF1-DNMT1可能参与甲基化的维持。据此，我们假设：发育早期的氧化应激通过H3K9me3-UHRF1-DNMT1维持Nrf2基因甲基化，导致Nrf2表达下调、阻力血管重塑和高血压。我们将对Nrf2启动子、SHR子鼠和血管平滑肌细胞进行甲基化修饰和抑制来明确甲基化调控Nrf2表达的作用。通过体内外分子功能获得和缺失实验重点阐明H3K9me3-UHRF1-DNMT1是Nrf2基因甲基化可遗传的分子机制。本项目将为解析“发育程序化”高血压的表观遗传新机制奠定基础。

氧化应激在高血压阻力血管重塑中发挥重要作用，核因子E2相关因子2（Nrf2）是体内主要的抗氧化因子。本项目主要目的是明确Nrf2在高血压阻力血管重塑中的作用，进一步证实DNMT1介导的Nrf2启动子甲基化是高血压阻力血管Nrf2表达下降的原因。结果发现与正常血压的Wistar Kyoto大鼠相比，自发性高血压大鼠（SHR）的肠系膜动脉中的Nrf2表达下降，DNMT1的表达上调。同时蛋白组学显示Nrf2的下游分子谷胱甘肽S-转移酶、血红素加氧酶1、NADPH：醌氧化还原酶 1表达下降。另外，在高血压左室肥厚病理过程中，通过蛋白组学我们发现外源物质分解代谢过程、胆固醇结合和线粒体质子转运ATP合酶是最明显富集基因本体的生物学过程、分子功能和细胞组分，而外源物质分解代谢主要涉及氧化应激。该结果提示氧化应激在高血压阻力血管重塑和左室肥厚的重要作用，同时也提示表观遗传在高血压相关阻力血管重塑可能发挥一定的作用。

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