BACKGROUND The mechanism of pyruvate kinase M2 (PKM2)-mediated inflammatory signalling in macrophages when plaques rupture and the impact of hyperglycaemia on the signalling are unclear. The present study aimed to explore the impact of hyperglycaemia on PKM2-mediated NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome/stress granule signalling in macrophages and its correlation with plaque vulnerability in vivo and in vitro. METHODS From July to December 2019, 80 patients with coronary heart disease (CHD) were divided into acute ST-segment elevation myocardial infarction (STEMI) (n = 57) (DM-STEMI, n = 21; non-DM-STEMI, n = 36) and stable CHD (SCHD) groups (n = 23). Circulating mononuclear cells were isolated. The value of peak troponin I (TnI), the Global Registry of Acute Coronary Events (GRACE) risk score, and the expression levels of the related markers were quantified and compared. In vitro studies on the THP-1 cells were also performed. RESULTS The DM-STEMI group had a higher value of peak TnI and a higher GRACE risk score than the non-DM-STEMI group (p < 0.05). The highest expression levels of PKM2, NLRP3, interleukin (IL)-1β, and IL-18 and the lowest expression level of GTPase activating protein (SH3 domain)-binding protein 1 (G3BP1) (a stress granule marker protein) were observed in the DM-STEMI group, and they were followed by the non-DM-STEMI group and the SCHD group (p < 0.05). In vitro studies showed similar results and that TEPP-46 (a PKM2 activator) and 2-deoxy-d-glucose (a toxic glucose analogue) reversed the hyperglycaemia-induced increase in the NLRP3 inflammasome and decrease in G3BP1 expression. CONCLUSION Hyperglycaemia might increase the activation of PKM2-mediated NLRP3 inflammasome/stress granule signalling and increase plaque vulnerability, associating it with worse prognosis. PKM2 may be a novel prognostic indicator and a new target for the treatment of patients with CHD and DM.

中文翻译：

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高血糖对巨噬细胞中 PKM2 介导的 NLRP3 炎症小体/应激颗粒信号传导的影响及其与斑块易损性的相关性：一项体内和体外研究。


背景 斑块破裂时丙酮酸激酶 M2 (PKM2) 介导的巨噬细胞炎症信号传导机制以及高血糖对信号传导的影响尚不清楚。本研究旨在探讨高血糖对巨噬细胞中PKM2介导的NOD样受体家族pyrin结构域3（NLRP3）炎症小体/应激颗粒信号传导的影响及其与体内和体外斑块脆弱性的相关性。方法 2019年7月至12月，80例冠心病（CHD）患者分为急性ST段抬高型心肌梗死（STEMI）（n = 57）（DM-STEMI，n = 21；非DM-STEMI，n = 36) 和稳定冠心病 (SCHD) 组 (n = 23)。分离循环单核细胞。对峰值肌钙蛋白 I (TnI) 值、全球急性冠脉事件登记 (GRACE) 风险评分以及相关标志物的表达水平进行量化和比较。还对 THP-1 细胞进行了体外研究。结果 DM-STEMI 组比非 DM-STEMI 组具有更高的 TnI 峰值和更高的 GRACE 风险评分（p < 0.05）。 PKM2、NLRP3、白细胞介素 (IL)-1β 和 IL-18 的表达水平最高，GTPase 激活蛋白（SH3 结构域）结合蛋白 1 (G3BP1)（一种应激颗粒标记蛋白）的表达水平最低。 DM-STEMI 组，其次是非 DM-STEMI 组和 SCHD 组（p < 0.05）。体外研究显示了类似的结果，TEPP-46（一种 PKM2 激活剂）和 2-脱氧-d-葡萄糖（一种有毒葡萄糖类似物）逆转了高血糖诱导的 NLRP3 炎性体增加和 G3BP1 表达减少。 结论 高血糖可能会增加 PKM2 介导的 NLRP3 炎症小体/应激颗粒信号的激活，增加斑块的脆弱性，从而导致较差的预后。 PKM2可能成为CHD和DM患者治疗的新预后指标和新靶点。