Department of Cardiology, Xuanwu Hospital, Capital Medical University, National Clinical Research Centre for Geriatric Diseases, Beijing 100053, China.
Department of Occupational and Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang 110122, China.
Metabolism. 2020 Jun;107:154231. doi: 10.1016/j.metabol.2020.154231. Epub 2020 Apr 13.
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.
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.
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.
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.
斑块破裂时，丙酮酸激酶 M2 (PKM2) 介导的巨噬细胞炎症信号转导的机制以及高血糖对信号转导的影响尚不清楚。本研究旨在探讨高血糖对巨噬细胞中 NOD 样受体家族富含吡啶结构域蛋白 3 (NLRP3) 炎性小体/应激颗粒信号转导的影响及其与体内和体外斑块易损性的相关性。
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）组（n=57）（DM-STEMI 组，n=21；非 DM-STEMI 组，n=36）和稳定型 CHD（SCHD）组（n=23）。分离循环单核细胞。定量比较各组患者肌钙蛋白 I 峰值（TnI）、全球急性冠状动脉事件注册（GRACE）风险评分和相关标志物的表达水平。还对 THP-1 细胞进行了体外研究。
DM-STEMI 组患者 TnI 峰值和 GRACE 风险评分均高于非 DM-STEMI 组（p<0.05）。DM-STEMI 组 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）（应激颗粒标记蛋白）的表达水平最低，而非 DM-STEMI 组和 SCHD 组次之（p<0.05）。体外研究结果也相似，并且 PKM2 激活剂 TEPP-46 和毒性葡萄糖类似物 2-脱氧-D-葡萄糖（2-deoxy-d-glucose）可逆转高血糖诱导的 NLRP3 炎性小体激活增加和 G3BP1 表达降低。
高血糖可能会增加 PKM2 介导的 NLRP3 炎性小体/应激颗粒信号转导的激活，增加斑块易损性，与预后不良相关。PKM2 可能是 CHD 和 DM 患者新的预后标志物和治疗靶点。
