Apelin/APJ系统通过调控肌醇需求酶1α依赖的自噬抑制脑缺血再灌注损伤的机制研究

During endoplasmic reticulum stress, inositol-requiring enzyme 1α(IRE1α)-dependent autophagy plays an important role in the angiogenesis and neuronal survival of ischemic penumbra of ischemic stroke (IS). Apelin is the endogenous ligand for the G protein-coupled receptor, APJ, which is neuroprotective in the acute and chronic neuronal damage. We have found that Apelin/APJ system inhibited the neuronal apoptosis and improved the behavioral and cognitive function in the models of IS through the regulation of PERK-eIF2α-ATF4-CHOP signaling pathway. However, it has not yet been reported whether or not IRE1α-dependent autophagy is involved in the neuroprotection of Apelin/APJ system . Therefore, we make a proposal that IRE1α-dependent autophagy is regulated by Apelin/APJ system , which promotes the angiogenesis of the penumbra of IS, enhances the regional cerebral blood flow, inhibits the neuronal apoptosis and then restores neuronal cognitive function. This contributes to the therapy of IS. Based on the previous our studies, we would investigate the effects of Apelin/APJ system on the activation of IRE1α-dependent autophagy in the vascular endothelial cells and neurons in IS. And the critical proteins in IRE1α-dependent autophagy is further investigated in the promotion of angiogenesis and neuronal survival of the penumbra of IS. The purpose of the present work is to provide the evidence for the therapies of Apelin/APJ system for IS experimentally.

内质网应激（ERS）过程中肌醇需求酶1α（IRE1α）依赖的自噬在脑缺血再灌注（I/R）损伤中血管新生和神经元存活中发挥重要作用。Apelin/APJ系统具有神经保护作用。我们研究表明：在I/R损伤中，Apelin/APJ系统通过调节ERS抑制了脑I/R损伤模型神经元凋亡，改善了行为学和认知功能，而Apelin/APJ系统对IRE1α依赖的自噬是否具有调节作用还未见相关报道。我们推测：Apelin/APJ系统通过调节IRE1α依赖的自噬促进脑I/R损伤中血管新生和神经元存活，提高神经和认知功能，从而达到治疗的目的。因此，本课题研究Apelin/APJ系统对脑I/R损伤中血管内皮细胞和神经元内IRE1α依赖的自噬活化的影响，并分析IRE1α依赖的自噬中关键分子在Apelin/APJ系统促进血管新生和神经元存活的机制，为Apelin/APJ系统治疗缺血性脑卒中提供实验基础和理论依据。

Apelin 是 1998 年由 Tatemoto 等首次从牛分泌物中提取并纯化的，人类、大鼠、小鼠和牛的 apelin mRNA 均编码含有 77 个氨基酸的 Apelin 原前体肽，其氨基酸序列在各物种间具有高度同源性。Apelin 原前体肽可以水解成多个不同长度的肽段如 Apelin-12、Apelin-13、Apelin-17 和 Apelin-36，上述肽段的受体均为血管紧张素 1 型受体相关蛋白（putative receptor protein related to the angiotensin receptor AT1，APJ），与之结合以后，发挥生物学效应，其中，Apelin-13 和 Apelin-36 与 APJ 亲和力和生物活性较强，在中枢神经系统急慢性神经元损伤中具有神经保护作用。本研究证实：Apelin（Apelin-13 和 Apelin-36）对脑缺血再灌注损伤模型具有神经保护作用，抑制了神经元凋亡，减轻了氧化应激，降低了自噬，sirt1介导的PINK1/ parkin、Bcl-2和PI3K/Akt/mTOR等信号通路参与了Apelin的神经保护作用。另外，Apelin对通过抑制AKT-mTOR信号通路来防止氧糖剥夺/再灌注对小鼠脑微血管内皮细胞bEnd.3损伤，促进了细胞迁移，表明Apelin具有促进血管新生的作用，综上所述，Apelin通过抑制缺血半暗带神经元死亡和促进血管新生起到神经保护作用。