“血糖记忆”效应引发大血管内皮细胞加速衰老的分子机制和预警干预策略研究

Atherosclerosis, which underlies a variety of vascular diseases, is characterized as chronic disturbance in vascular homeostasis and remodeling. In the last decades, diabetes-induced chronic hyperglycemia has been demonstrated to accelerate atherogenesis. Recently, glycemic memory, referred as the prolonged harm produced by transient hyperglycemic stimulation, has been implicated in both clinical and fundamental researches. However, the mechanisms that glycemic memory on promoting atherogenesis still remains mostly unknown. Our previous findings indicated that miR-34a/SIRT-1/acetyl-p53 positive regulatory loop was involved in glycemic memory, and metformin could significantly ameliorate glycemic memory by inhibiting this positive regulation. Moreover, we also found that circulating miR-34a could reflect the promotion of this phenomenon. Therefore, in this study, we aim to extensively explore the intracellular and extracellular mechanisms of miR-34a/SIRT-1/acetyl-p53-mediated regulations on facilitating glycemic memory, so as to enhance our understandings on vascular homeostasis and remodeling, and to provide novel avenues for early detection and effective prevention of the vascular diseases.

动脉粥样硬化是血管稳态和重构失衡的典型表现，糖尿病引发的糖脂代谢紊乱显著加速动脉粥样硬化的发生和发展。最新的研究表明，短期的高糖刺激即可引发持续加速的血管病变，即“血糖记忆”现象。然而，目前尚不明确“血糖记忆”引发动脉粥样硬化加速发展的分子机制。本课题组的前期研究已初步揭示，miR-34a/SIRT-1/acetyl-p53正反馈通路与大血管内皮细胞衰老的 “血糖记忆”现象存在共变关系，而二甲双胍或可通过阻断上述机制延缓“血糖记忆”现象的发展。此外，循环miR-34a或可反映“血糖记忆”现象的进展程度，高度提示miR-34a介导的胞内和胞外分子机制可能是“血糖记忆”的核心调控环节。因此，本课题拟，深入探索miR-34a/SIRT-1/acetyl-p53正反馈通路引发内皮衰老“血糖记忆”现象的胞内和胞外分子机制，以期为今后血管稳态与重构相关的基础研究提供新的研究思路和预警干预靶点。

动脉粥样硬化是血管稳态和重构失衡的典型表现，糖尿病引发的糖脂代谢紊乱显著加速动脉粥样硬化的发生和发展。最新的研究表明，短期的高糖刺激即可引发持续加速的血管病变，即“血糖记忆”现象。然而，目前尚不明确“血糖记忆”引发动脉粥样硬化加速发展的分子机制。血糖记忆”现象存在共变关系，而二甲双胍或可通过阻断上述机制延缓“血糖记忆”现象的发展。本研究中我们首先在细胞水平开展探索性研究，初步揭示“血糖记忆”现象的调控方式；随后，我们同时在动物水平和人体水平开展验证性研究，证实SIRT-1/acetyl-p53 调控是引发“血糖记忆”现象的分子机制。长链非编码RNA（lncRNA）在糖尿病血管并发症的形成中发挥了至关重要的调控作用。我们通过测序发现了多个在高糖刺激下表达上调的新的lncRNA。其中，lncRNA GIVER不仅与其邻居基因NR4a3相互调控，并有可能通过上调NOX1、Ccl2、Cyclin D1等分子的转录表达，密切参与血管平滑肌细胞的氧化应激、炎症反应和细胞增殖效应。此外，二甲双胍干预能够显著下调GIVER，强烈提示GIVER可能是糖尿病继发血管并发症的关键调控靶标，这或许是糖尿病血管并发症的新的分子通路和干预靶标，以期为今后血管稳态与重构相关的基础研究提供新的研究思路和预警干预靶点。