NOSH-NBP通过SIRT1脱乙酰化作用调控HMGB1核质转运改善心跳骤停复苏后血脑屏障损伤的机制研究

心肺复苏（CPR）后血脑屏障（BBB）破坏可导致患者神经功能受损甚至致残、致死，缺乏有效防治手段。文献报道，高迁移率族蛋白B1（HMGB1）的活性受脱乙酰化酶（SIRT1）调控，可能参与局灶性脑损伤后BBB通透性的调控，但机制不明。NO和H2S是体内重要的气体递质分子，本课题组前期证明H2S的神经保护作用与抑制BBB损伤相关。H2S和NO能否发挥协同作用，引起我们关注。预实验显示，H2S和NO释放剂NOSH-NBP减轻CPR后BBB破坏，且与下调Ac-HMGB1相关。鉴此，我们推测H2S和NO通过协同上调SIRT1脱乙酰化调控HMGB1核质转运，减轻CPR后BBB损伤。本项目构建体外BBB糖氧剥夺和大鼠室颤CPR模型，采用基因沉默、影像学和免疫学等技术，验证上述科学假设。研究结果将进一步揭示CPR后BBB损伤以及H2S和NO协同脑保护的分子机制，为防治CPR后脑损伤提供新的靶点和治疗策略。

The damage of the blood-brain barrier (BBB) is an important cause of neurological dysfunction, disability and death after cardiac arrest and cardiopulmonary resuscitation (CPR), and there is no effective therapy in clinic. Recent studies have shown that high mobility group box 1 (HMGB1) is regulated by a deacetylase named silent mating type information regulation 2 homolog 1 (SIRT1) and involves in the permeability of BBB after focal cerebral injury. However, the mechanism is still unknown. Nitric Oxide (NO) and hydrogen sulfide (H2S) are important gas transmitters in the body. Our previous studies confirmed that exogenous H2S reduced the damage of BBB and improved the neurological function after CPR. Whether the synergistic effect of H2S and NO plays a greater role in cerebral protection after CPR attracts our attention. Furthermore, in the pre-experiment, we demonstrated that NOSH-NBP, a releasing agent of NO and H2S, alleviated the injury of BBB after CPR and this effect was related to the down-regulation of Ac-HMGB1. On the basis of these previous works, this project proposes the scientific hypothesis that the synergistic effect of H2S and NO reduces BBB damage after CPR through deacetylation and nucleocytoplasmic transport of HMGB1, which is mediated by up-regulation of SIRT1. The BBB under glucose oxygen deprivation model and rat ventricular fibrillation and CPR model will be established in this project. We will use the gene silencing, imaging, and immunology techniques to clarify the mechanism of NOSH-NBP in inhibiting the damage of BBB. The results of this research will further reveal the mechanisms of BBB damage after CPR and the synergistic effect of H2S and NO. It will also provide new target and therapeutic strategy for improving the neurological function of patients with CPR.