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促进的无菌炎症与心肌梗塞 (MI) 后的心脏功能障碍密切相关。糖原合酶激酶 3 (GSK-3β) 是炎症反应的重要介质，高 GSK-3 活性与各种心脏病有关。我们在第 2-28 天成功诱导 MI 的大鼠模型中研究了 GSK-3β 在激活包含 3（NLRP3）炎性体的 nod 样受体家族 pyrin 结构域的调节机制。在典型的炎性体刺激和缺氧治疗下，使用新生大鼠/人心肌细胞和成纤维细胞培养物进行了体外研究。GSK-3β 抑制显着改善心肌功能障碍并阻止重构，同时降低 MI 后 NLRP3 炎性体激活的参数。GSK-3β 抑制降低了心脏成纤维细胞中 NLRP3 炎性体的激活，但在心肌细胞中没有。GSK-3β 与激活信号协整器 (ASC) 的相互作用以及 GSK-3β 抑制降低了组织和细胞水平上的 ASC 磷酸化和寡聚化。总之，这些数据表明 GSK-3β 直接介导 NLRP3 炎性体激活，导致 MI 中的心脏功能障碍。