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

Metabolism. 2020 Jun:107:154231. doi: 10.1016/j.metabol.2020.154231. Epub 2020 Apr 13.

Abstract

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.

Keywords: Diabetes mellitus; Hyperglycaemia; NLRP3 inflammasome; PKM2; Plaque vulnerability; Stress granule.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Carrier Proteins / metabolism*
  • Cell Line
  • Coronary Disease / metabolism
  • Cytoplasmic Granules*
  • DNA Helicases / blood
  • Female
  • Humans
  • Hyperglycemia / chemically induced
  • Hyperglycemia / physiopathology*
  • Inflammasomes*
  • Interleukins / blood
  • Macrophages / metabolism*
  • Male
  • Membrane Proteins / metabolism*
  • Middle Aged
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Plaque, Atherosclerotic / metabolism*
  • Poly-ADP-Ribose Binding Proteins / blood
  • RNA Helicases / blood
  • RNA Recognition Motif Proteins / blood
  • ST Elevation Myocardial Infarction / metabolism
  • Thyroid Hormone-Binding Proteins
  • Thyroid Hormones / metabolism*
  • Troponin I / metabolism

Substances

  • Carrier Proteins
  • Inflammasomes
  • Interleukins
  • Membrane Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Poly-ADP-Ribose Binding Proteins
  • RNA Recognition Motif Proteins
  • Thyroid Hormones
  • Troponin I
  • DNA Helicases
  • G3BP1 protein, human
  • RNA Helicases