Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Undergraduate, Student of Class 2015, Department of Clinical Medicine, Zhengzhou University, Zhengzhou 450052, China.
J Mol Cell Cardiol. 2020 Dec;149:82-94. doi: 10.1016/j.yjmcc.2020.09.009. Epub 2020 Sep 28.
Inflammasome-promoted sterile inflammation following cardiac damage is critically implicated in heart dysfunction after myocardial infarction (MI). Glycogen synthase kinase-3 (GSK-3β) is a prominent mediator of the inflammatory response, and high GSK-3 activity is associated with various heart diseases. We investigated the regulatory mechanisms of GSK-3β in activation of the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in a rat model with successful induction of MI on days 2-28. An in vitro investigation was performed using newborn rat/human cardiomyocytes and fibroblast cultures under typical inflammasome stimulation and hypoxia treatment. GSK-3β inhibition markedly improved myocardial dysfunction and prevented remodeling, with parallel reduction in the parameters of NLRP3 inflammasome activation after MI. GSK-3β inhibition reduced NLRP3 inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes. GSK-3β's interaction with activating signal cointegrator (ASC) as well as GSK-3β inhibition reduced ASC phosphorylation and oligomerization at the tissues and cellular levels. Taken together, these data show that GSK-3β directly mediates NLRP3 inflammasome activation, causing cardiac dysfunction in MI.
心脏损伤后炎症小体诱导的无菌性炎症在心肌梗死后心脏功能障碍中起关键作用。糖原合酶激酶-3（GSK-3β）是炎症反应的主要介质，高 GSK-3 活性与各种心脏病有关。我们在成功诱导心肌梗死后 2-28 天的大鼠模型中研究了 GSK-3β 在 NOD 样受体家族含 pyrin 域蛋白 3（NLRP3）炎症小体激活中的调节机制。使用新生大鼠/人心肌细胞和成纤维细胞培养物进行体外研究，在典型的炎症小体刺激和低氧处理下进行。GSK-3β 抑制显著改善心肌功能障碍并预防重塑，MI 后 NLRP3 炎症小体激活的参数也平行降低。GSK-3β 抑制可减少心肌成纤维细胞中的 NLRP3 炎症小体激活，但不能减少心肌细胞中的 NLRP3 炎症小体激活。GSK-3β 与激活信号整合子（ASC）的相互作用以及 GSK-3β 抑制可减少组织和细胞水平 ASC 的磷酸化和寡聚化。总之，这些数据表明 GSK-3β 直接介导 NLRP3 炎症小体激活，导致 MI 中的心脏功能障碍。
