Jin Wei, Xu Wei, Zhang Xiaoxiao, Ren Chuan-Cheng
Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.
Department of Neurology, Affiliated Hospital of Nantong University, No. 20 Xisi Road, Nantong, 226001, Jiangsu Province, People's Republic of China.
Mol Neurobiol. 2020 Sep;57(9):3658-3670. doi: 10.1007/s12035-020-01978-3. Epub 2020 Jun 20.
As ischemic preconditioning (IPC) represents a potential therapy against cerebral ischemia, the purpose of the present study is to explore the molecular mechanisms of ischemic preconditioning induced cerebral protective effect. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, which induces apoptosis through binding to its death receptors (DR4 and DR5). When TRAIL binds to decoy receptors (DcR1 and DcR2), as DcRs lack intact cytoplasmic death domain, TRAIL fails to induce neuronal apoptosis. In the present study, we demonstrated that ischemic preconditioning upregulated DcR1 and DcR2, which subsequently inhibited oxygen glucose deprivation-induced cellular apoptosis. Then, we investigated the protective molecular mechanism of DcRs after ischemic preconditioning treatment. Results showed that DcR1 could competitively bind to TRAIL and partially inhibit TRAIL-induced cellular apoptosis. On the other hand, DcR2 could disturb DRs-associated death-inducing signaling complex formation (DISC), which further inhibited capase-8 activation. Besides, we also found that ischemic preconditioning activated IPC-induced Akt phosphorylation via regulating DcR2 level. Thus, ischemic preconditioning upregulated decoy receptors, which protected cells from oxygen glucose deprivation-induced cellular damage by inhibiting TRAIL-induced apoptosis and agitating PI3K/Akt pathway. Our data complemented the knowledge of neuroprotective mechanism of ischemic preconditioning and provided new evidence for supporting its clinical application.
由于缺血预处理（IPC）是一种针对脑缺血的潜在治疗方法，本研究的目的是探讨缺血预处理诱导脑保护作用的分子机制。肿瘤坏死因子相关凋亡诱导配体（TRAIL）是肿瘤坏死因子超家族的成员，它通过与其死亡受体（DR4和DR5）结合诱导细胞凋亡。当TRAIL与诱饵受体（DcR1和DcR2）结合时，由于DcR缺乏完整的细胞质死亡结构域，TRAIL无法诱导神经元凋亡。在本研究中，我们证明缺血预处理上调了DcR1和DcR2，随后抑制了氧糖剥夺诱导的细胞凋亡。然后，我们研究了缺血预处理后DcR的保护分子机制。结果表明，DcR1可以竞争性结合TRAIL并部分抑制TRAIL诱导的细胞凋亡。另一方面，DcR2可以干扰与死亡受体相关的死亡诱导信号复合物（DISC）的形成，进一步抑制半胱天冬酶-8的激活。此外，我们还发现缺血预处理通过调节DcR2水平激活IPC诱导的Akt磷酸化。因此，缺血预处理上调了诱饵受体，通过抑制TRAIL诱导的凋亡和激活PI3K/Akt途径保护细胞免受氧糖剥夺诱导的细胞损伤。我们的数据补充了缺血预处理神经保护机制的知识，并为支持其临床应用提供了新的证据。
