The impact of hyperglycaemia on PKM2-mediated NLRP3 inflammasome/stress granule signalling in macrophages and its correlation with plaque vulnerability: an in vivo and in vitro study

Abstract

BackgroundThe 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. MethodsFrom 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. ResultsThe 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. ConclusionHyperglycaemia 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.