Metformin protects against intestinal ischemia-reperfusion injury and cell pyroptosis via TXNIP-NLRP3-GSDMD pathway
Metformin protects against intestinal ischemia-reperfusion injury and cell pyroptosis via TXNIP-NLRP3-GSDMD pathway
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DOI：
10.1016/j.redox.2020.101534
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发表时间：
2020-05-01
期刊：
影响因子：
11.4
通讯作者：
Zhang, Jingyao
中科院分区：
文献类型：
--
作者：
Jia, Yifan;Cui, Ruixia;Zhang, Jingyao
肠缺血再灌注损伤是一种严重威胁生命的血管急症，一直是困扰外科医生的难题。氧化应激被认为是I/R损伤的重要因素。美托洛尔具有抗氧化特性，可防止I/R损伤。本研究旨在探讨二甲双胍对肠I/R损伤的保护作用及其机制。通过暂时性上级肠系膜动脉阻断诱导小鼠I/R损伤，并对Caco-2细胞进行OGD/R建立体外模型。在体内和体外给予不同剂量的二甲双胍。我们通过检查组织病理学结果和肠屏障指数，包括TER、紧密连接蛋白和血清生物标志物，发现I/R损伤导致肠屏障破坏和细胞死亡。我们证实了在肠I/R损伤中存在焦亡。此外，我们通过沉默gasdermin D（GSDMD）证实了焦亡在肠I/R损伤中的作用。然后，我们证实了二甲双胍治疗保护屏障功能免受肠I/R损伤，并减少氧化应激和炎症反应。重要的是，二甲双胍减少了热解相关蛋白，包括NLRP 3，裂解的caspase-1和GSDMD的N-末端。敲低GSDMD可逆转Metastrophic的保护作用，说明在肠I/R损伤的情况下，焦亡是Metastrophic调控的主要细胞死亡途径之一。我们还发现，Metabolic抑制TXNIP的表达和TXNIP和NLRP 3之间的相互作用。我们进行了siRNA敲除，发现保护作用被消除，这进一步证实了我们的发现。总之，我们认为，二甲双胍以TXNIP-NLRP 3-GSDMD依赖的方式保护肠I/R损伤。
Intestinal ischemia-reperfusion (I/R) injury is a life-threatening vascular emergency and has long been a disturbing problem for surgeons. Oxidative stress is considered a vital factor in I/R injury. Metformin has antioxidative properties and protects against I/R injury. The present study aimed to investigate whether Metformin protects against intestinal I/R injury and reveal the protective mechanism of Metformin. I/R injury was induced in mice by temporary superior mesenteric artery occlusion, and Caco-2 cells were subjected to OGD/R to establish an in vitro model. Different doses of Metformin were administered in vivo and in vitro. We found that I/R injury led to intestinal barrier disruption and cell death by examining histopathological results and the intestinal barrier index, including TER, tight junction proteins and serum biomarkers. We confirmed the existence of pyroptosis in intestinal I/R injury. Moreover, we confirmed the role of pyroptosis in intestinal I/R injury by silencing the gasdermin D (GSDMD). Then, we confirmed that Metformin treatment protected barrier function against intestinal I/R injury and reduced oxidative stress and the inflammatory response. Importantly, Metformin reduced pyroptosis-related proteins, including NLRP3, cleaved caspase-1, and the N-terminus of GSDMD. Knocking down the GSDMD could reversed the protective effects of Metformin, which showed pyroptosis was one of the major cell death pathways controlled by Metformin treatment in setting of intestinal I/R injury. We also discovered that Metformin suppressed the expression of TXNIP and the interaction between TXNIP and NLRP3. We performed siRNA knockdown and found that the protective effects were abolished, which further confirmed our findings. In conclusion, we believe that Metformin protects against intestinal I/R injury in a TXNIP-NLRP3-GSDMD-dependent manner.