内质网应激PERK信号通路介导Nrf2/ARE-HO-1轴调控在心肌缺血再灌注损伤中的作用研究

Previous studies demonstrated that the endoplasmic reticulum stress (ERS) may play an important role during myocardial ischemia and reperfusion (I/R) injury. Interestingly, according to the latest research, ERS-mediated protein kinase R-like ER kinase (ERS-PERK) signaling pathway may involve in activating nuclear factor-erythroid 2-related factor 2 (Nrf2) and play an important role for attenuating ERS in PC12 cells, which may be related to the induction of heme oxygenase-1(HO-1). In addition, our previous studies have demonstrated that Nrf2/antioxidant response element (ARE)-mediated HO-1 induction (Nrf2/ARE-HO-1 axis) may play an important role for attenuating myocardial I/R injury. However, the regulatory relationships between ERS-PERK signaling pathway and Nrf2/ARE-HO-1-axis during myocardial I/R injury still remain unclear. Taken together, basing on previous studies, the first aim of the present study was to investigate the regulatory relationships between ERS-PERK signaling pathway and Nrf2/ARE-HO-1 axis during myocardial ischemia and reperfusion injury, and the second aim of the present study was to investigate the feedback effects of strengthening PERK-mediated Nrf2/ARE-HO-1 axis regulation on ERS during myocardial I/R injury, expecting to provide new ideas and strategies for the prevention and therapy of myocardial I/R injury.

内质网应激在心肌缺血再灌注(I/R)损伤中扮演重要角色。最近研究进一步显示，在PC12细胞中，内质网应激PERK信号通路参与激活核因子-E2相关因子2（Nrf2），进而有效缓解细胞的内质网应激状态，推测其作用机制可能与介导血红素加氧酶-1（HO-1）的表达增加有关。我们前期研究发现，激活Nrf2/ARE信号通路可介导HO-1的过表达（即Nrf2/ARE-HO-1轴），进而在心肌I/R损伤中发挥重要保护作用。但是，内质网应激PERK信号通路与Nrf2/ARE-HO-1轴在心肌I/R损伤中的相关调控关系仍不明确。在本研究中，我们首先探究内质网应激PERK信号通路与Nrf2/ARE-HO-1轴在心肌I/R损伤中可能存在的调控关系；然后进一步研究强化PERK信号通路介导Nrf2/ARE-HO-1轴调控对心肌I/R损伤中内质网应激的反馈性影响，以期有助于为防治心肌I/R损伤提供新的思路和策略。

内质网应激在心肌缺血再灌注(I/R)损伤中扮演重要角色，故有效调控内质网应激将有望成为防治心肌I/R损伤的新思路。最近研究显示，在PC12细胞中，内质网应激PERK信号通路参与激活转录因子Nrf2并伴有内质网应激状态的有效缓解，推测在一定程度上可能与介导血红素加氧酶-1（HO-1）的表达增加相关，但具体调控机制有待进一步论证。我们前期研究发现，激活Nrf2/ARE信号通路可介导HO-1的过表达（即Nrf2/ARE-HO-1轴），进而在心肌I/R损伤中发挥重要保护作用，但其是否与内质网应激PERK信号通路在心肌I/R损伤中存在相关调控关系仍不明确。综上原因，我们开展本研究项目并获得相关研究结果：第一，我们研究结果表明内质网应激PERK信号通路与Nrf2/ARE-HO-1轴在心肌I/R损伤中存在的调控关系；第二，我们的研究数据进一步论证强化PERK信号通路介导Nrf2/ARE-HO-1轴调控对心肌I/R损伤中内质网应激的反馈性影响和作用机制；本研究项目的科学意义在于进一步阐明并丰富心肌 I/R 损伤的重要机制，为预防和治疗心肌 I/R 损伤提供新思路和新策略。