Peroxynitrite activates NLRP3 inflammasome and contributes to hemorrhagic transformation and poor outcome in ischemic stroke with hyperglycemia
Peroxynitrite activates NLRP3 inflammasome and contributes to hemorrhagic transformation and poor outcome in ischemic stroke with hyperglycemia
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DOI：
10.1016/j.freeradbiomed.2021.01.030
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发表时间：
2021-02-04
影响因子：
7.4
通讯作者：
Shen, Jiangang
中科院分区：
文献类型：
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作者：
Chen, Hansen;Guan, Binghe;Shen, Jiangang
本研究旨在验证过氧亚硝酸盐介导的炎性小体激活可能是血脑屏障（BBB）破坏、出血性转化（HT）和缺血性卒中伴高血糖不良结局的关键因素这一假设。我们使用了一个实验性大鼠中风模型进行90分钟的大脑中动脉闭塞加24小时或7天的再灌注与或不急性高血糖。检测脑缺血后过氧亚硝基阴离子的产生、NADPH氧化酶、iNOS、MMPs和NLRP 3炎性小体的表达，并评价脑梗死体积、脑水肿、HT、神经功能缺损评分和存活率。我们的研究结果表明：（1）高脂血症可增加NADPH氧化酶亚基p47 phox和p67 phox的表达，增加iNOS的表达，增加过氧亚硝基阴离子的产生。(2)高血压增加梗死体积，加重BBB通透性增高，诱导脑水肿和HT，并使神经功能结局恶化。这些脑损伤和不良结局可通过FeTmPyP（一种代表性的过氧亚硝酸盐分解催化剂，PDC）、过氧亚硝酸盐清除剂尿酸和iNOS抑制剂1400 W的治疗逆转。PDC和1400 W均能抑制MMPs和NLRP 3炎性小体（包括pro/activ-caspase-1和IL-113）的激活，提示过氧亚硝基阴离子在高血糖诱导的缺血脑MMPs和NLRP 3炎性小体中起作用。(3)NLRP 3炎性体抑制剂MCC 950、半胱天冬酶-1抑制剂VX-765和IL-113抑制剂双醋瑞因减轻了脑水肿，最小化了出血转化并改善了神经学结果，证明了NLRP 3炎性体在伴有急性高血糖的缺血性卒中大鼠中的高血糖介导的HT和不良结果中的作用。结论：过氧亚硝基阴离子可介导MMPs和NLRP 3炎性体的活化，加重血脑屏障损伤和HT，导致高血糖缺血性脑卒中预后不良。因此，针对过氧亚硝酸盐？NLRP 3介导的炎性体可能是缺血性卒中伴高血糖的一种有前途的策略。
This study aims to test the hypothesis that peroxynitrite-mediated inflammasome activation could be a crucial player in the blood-brain barrier (BBB) disruption, hemorrhagic transformation (HT) and poor outcome in ischemic stroke with hyperglycemia. We used an experimental rat stroke model subjected to 90 min of middle cerebral artery occlusion plus 24 h or 7 days of reperfusion with or without acute hyperglycemia. We detected the production of peroxynitrite, the expression of NADPH oxidase, iNOS, MMPs and NLRP3 inflammasome in the ischemic brains, and evaluated infarct volume, brain edema, HT, neurological deficit score and survival rates. Our results show that: (1) Hyperglycemia increased the expression of NADPH oxidase subunits p47phox and p67phox, and iNOS, and the production of peroxynitrite. (2) Hyperglycemia increased infarct volume, aggravated the BBB hyperpermeability, induced brain edema and HT, and worsened neurological outcomes. These brain damages and poor outcome were reversed by the treatments of FeTmPyP (a representative peroxynitrite decomposition catalyst, PDC), peroxynitrite scavenger uric acid, and iNOS inhibitor 1400W. Furthermore, the activations of MMPs and NLRP3 inflammasome including pro/active-caspase-1 and IL-113 were inhibited both PDC and 1400W, indicating the roles of peroxynitrite in the inductions of MMPs and NLRP3 inflammasome in the ischemic brains under hyperglycemia. (3) NLRP3 inflammasome inhibitor MCC950, caspase-1 inhibitor VX-765 and IL-113 inhibitor diacerein attenuated brain edema, minimized hemorrhagic transformation and improved neurological outcome, demonstrating the roles of NLRP3 inflammasome in the hyperglycemia-mediated HT and poor outcome in the ischemic stroke rats with acute hyperglycemia. In conclusion, peroxynitrite could mediate activations of MMPs and NLRP3 inflammasome, aggravate the BBB damage and HT, and induce poor outcome in ischemic stroke with hyperglycemia. Therefore, targeting peroxynitrite?mediated NLRP3 inflammasome could be a promising strategy for ischemic stroke with hyperglycemia.