高盐经AMPK/PGC-1α/SIRT3轴下调MnSOD产生“记忆效应”介导盐敏感内皮功能失调

Short-term exposure to high salt can affect long-term changes in blood pressure, resulting in vascular endothelium and other organ damage in salt-sensitive individuals. But the molecular mechanism remains unclear. Previous studies demonstrated that a “memory effect” can be induced by short-term salt intake and Manganese superoxide dismutase (MnSOD) plays an important role in salt-sensitive hypertension and endothelial dysfunction. Herein, we hypothesized that short-term high-salt intake cause continuously enhanced oxidative stress in endothelial cells through down-regulating MnSOD via AMPK/PGC-1α/SIRT3 pathway, causing a phenomenon of "salt memory", and thus mediating endothelial dysfunction in salt-sensitive rats. First, Dahl salt-sensitive rats were fed with short-term high salt diet or plus antioxidants intervention and then converted to a normal salt diet to investigate the effect of increased vascular oxidative stress and MnSOD on endothelial dysfunction in salt-sensitive hypertension. Second, the role of AMPK/PGC-1α/SIRT3/MnSOD pathway in the regulation of “salt memory” and NO imbalance was further elucidated at the cellular level with experimental techniques such as lentivirus-mediated gene silencing and overexpression, ChIP and other technologies. This work would help us further uncover the etiology of salt sensitive hypertension as well as seek the potential drug targets for treatment of essential hypertension.

盐敏感者短期高盐暴露可影响远期血压变化、造成血管内皮等靶器官损伤，阐明其生物学机制意义重大。本研究在前期发现短期高盐摄入可产生“记忆效应”及MnSOD在盐敏感性高血压和内皮功能失调中发挥重要作用的基础上，提出“短期高盐摄入通过AMPK/PGC-1α/SIRT3途径下调MnSOD导致血管内皮氧化应激水平持续性升高，产生“盐记忆”现象，介导盐敏感血管内皮功能失调”假说。首先对盐敏感大鼠进行短期高盐/高盐+MnSOD模拟物干预后转为正常盐干预，探索血管氧化应激和MnSOD在短期高盐诱导盐敏感内皮功能失调中的作用；在此基础上结合慢病毒介导的基因沉默/过表达、ChIP等技术，在细胞水平上阐明AMPK/PGC-1α/SIRT3/MnSOD途径在短期高盐致内皮细胞氧化应激水平持续性升高及后续NO失衡中的调控机制。该研究有助于揭示盐敏感性高血压的分子遗传学机制及识别潜在的药物治疗靶点。

盐是高血压的重要环境因素之一，参与高血压发生及其靶器官损伤。然而，短期高盐摄入是否会导致盐敏感者血压持续升高及靶器官损伤尚不清楚。本课题在既往盐敏感高血压发病机制研究的基础上，提出“盐敏感者短期高盐负荷诱导机体产生“盐记忆”，增加局部组织的氧化应激水平，最终导致盐敏感性高血压和内皮功能失调”的假设。首先以Dahl盐敏感性大鼠和SS-13BN大鼠为模型，结果发现在盐敏感性高血压中存在“盐记忆”效应，且氧化应激在“盐记忆”所致盐敏感内皮损伤中发挥重要作用；其次，通过动物实验和细胞研究发现炎症机制参与“盐记忆”介导盐敏感高血压肾损伤以及Set7/H3K4me1/Set7/H3K4me1/NF-κB P65途径在“盐记忆”效应中的介导作用；最后，基于人群队列的纵向随访数据，识别生命早期BP/BMI的演变轨迹，发现上述轨迹与远期高血压发生或成年阶段早期肾脏损伤存在关联。以上结果进一步阐明了盐敏感性高血压的发生机制，并为原发性高血压的人群防治提供了理论基础和新策略。