Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Pharmacol Res. 2024 Nov;209:107435. doi: 10.1016/j.phrs.2024.107435. Epub 2024 Sep 28.
Tissue kallikrein (TK) has emerged as a potential neuroprotective agent in ischemic stroke (IS), yet the optimal timing and mechanisms of TK therapy remain unclear. Here, we established a causal link between lower baseline TK levels and an increased risk of stroke through a retrospective, multicenter cohort study involving 2115 initially non-stroke subjects monitored for 5 years. Sequentially, we observed a notable increase in bradykinin receptor 2 (B2R) levels during the ischemic phase of the IS model, while levels of TK and bradykinin receptor 1 (B1R) remained stable. Intriguingly, both B1R and B2R exhibited a significant elevation 24 h after reperfusion. Further investigations in preclinical models demonstrated that TK supplementation activates the PI3K/AKT signaling pathway via enhanced B2R expression during the ischemic phase, leading to nuclear translocation of Hif-1α. This activation enhances the expression of VEGF and eNOS, thereby fortifying the neurovascular unit. Moreover, it suppresses the activation of the kallikrein-kinin system induced by reperfusion injury, effectively reducing inflammation, ROS production, apoptosis, and endothelial barrier dysfunction. Thus, our findings highlight the significance of TK supplementation during the ischemic phase in attenuating reperfusion-induced injury in IS, providing a mechanistic rationale for determining the optimal timing for TK supplementation therapy.
组织激肽释放酶 (TK) 已成为缺血性中风 (IS) 潜在的神经保护剂，但 TK 治疗的最佳时机和机制仍不清楚。在这里，我们通过一项涉及 2115 名最初非中风患者的回顾性多中心队列研究，建立了基线 TK 水平较低与中风风险增加之间的因果关系，这些患者在 5 年内进行了监测。随后，我们观察到在 IS 模型的缺血期 B2R 水平显著升高，而 TK 和 B1R 水平保持稳定。有趣的是，B1R 和 B2R 在再灌注后 24 小时均显著升高。在临床前模型中的进一步研究表明，TK 补充通过在缺血期增强 B2R 表达来激活 PI3K/AKT 信号通路，导致 Hif-1α 的核易位。这种激活增强了 VEGF 和 eNOS 的表达，从而增强了神经血管单元。此外，它还抑制了再灌注损伤引起的激肽释放酶-激肽系统的激活，有效减少了炎症、ROS 产生、细胞凋亡和内皮屏障功能障碍。因此，我们的研究结果强调了在缺血期补充 TK 以减轻 IS 再灌注引起的损伤的重要性，为确定 TK 补充治疗的最佳时机提供了机制依据。
