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. 2023 Dec 19;119(16):2653-2662.
doi: 10.1093/cvr/cvac184.

GLUT-1/PKM2 loop dysregulation in patients with non-ST-segment elevation myocardial infarction promotes metainflammation

Francesco Canonico  1 , Daniela Pedicino  1 , Anna Severino  2 , Ramona Vinci  1   2 , Davide Flego  2 , Eugenia Pisano  1 , Alessia d'Aiello  2 , Pellegrino Ciampi  2 , Myriana Ponzo  2 , Alice Bonanni  1   2 , Astrid De Ciutiis  2 , Sara Russo  2 , Marianna Di Sario  2 , Giulia Angelini  1   2 , Piotr Szczepaniak  3   4 , Alfonso Baldi  5 , Boguslaw Kapelak  6 , Karol Wierzbicki  6 , Rocco A Montone  1 , Domenico D'Amario  1 , Massimo Massetti  1   2 , Tomasz J Guzik  3   4 , Filippo Crea  1   2 , Giovanna Liuzzo  1   2
Affiliations

GLUT-1/PKM2 loop dysregulation in patients with non-ST-segment elevation myocardial infarction promotes metainflammation

Francesco Canonico et al. Cardiovasc Res. .

Abstract

Aims: The functional capacity of the immune cells is strongly dependent on their metabolic state and inflammatory responses are characterized by a greater use of glucose in immune cells. This study is aimed to establish the role of glucose metabolism and its players [glucose transporter 1 (GLUT-1) and pyruvate kinase isozyme M2 (PKM2)] in the dysregulation of adaptive immunity and inflammation observed in patients with non-ST-segment elevation myocardial infarction (NSTEMI).

Methods and results: We enrolled 248 patients allocated to three groups: NSTEMI patients, chronic coronary syndromes (CCS) patients, healthy subjects (HSs). NSTEMI patients showed higher expression of GLUT-1 and an enhanced glucose uptake in T cells when compared with CCS patients (P < 0.0001; P = 0.0101, respectively) and HSs (P = 0.0071; P = 0.0122, respectively). PKM2 had a prevalent nuclear localization in T lymphocytes in NSTEMI (P = 0.0005 for nuclear vs. cytoplasm localization), while in CCS and HS, it was equally distributed in both compartments. In addition, the nuclear fraction of PKM2 was significantly higher in NSTEMI compared with HS (P = 0.0023). In NSTEMI patients, treatment with Shikonin and Fasentin, which inhibits PKM2 enzyme activity and GLUT-1-mediated glucose internalization, respectively, led to a significant reduction in GLUT-1 expression along with the down-regulation of pro-inflammatory cytokine expression.

Conclusion: NSTEMI patients exhibit dysregulation of the GLUT-1/PKM2 metabolic loop characterized by nuclear translocation of PKM2, where it acts as a transcription regulator of pro-inflammatory genes. This detrimental loop might represent a new therapeutic target for personalized medicine.

Keywords: Acute coronary syndromes; Adaptive immunity; GLUT-1; Immuno-metabolism; Meta-inflammation; PKM2; Precision medicine.

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Conflict of interest statement

Conflict of interest: F.Cr. reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work. G.L. received grant support (to the institution) for investigator-initiated research from American Heart Association, Italian National Health Service, and Italian Minister of Education, University and Research. She is currently involved in the Research Programs of the Italian Cardiovascular Network. She received personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Sanofi, and Novartis, outside the submitted work.

Figures

Graphical Abstract
Graphical Abstract
GLUT-1/PKM2 metabolic loop and inflammatory pathways. PKM2 plays a central role in the modulation of the metabolic and inflammatory state. Our data showed aberrant localization of PKM2, in patients with NSTEMI, promoting enhanced GLUT-1 expression and glucose metabolism that shifts adaptive immunity towards a pro-inflammatory profile. The functional effects of the disruption of the metabolic loop GLUT-1/PKM2, through treatment with SKN and FSN in NSTEMI patients, led to a reduction of the pro-inflammatory profile and a modulation of the factors involved in lipid metabolism, contributing to the re-establishment of a physiological phenotype. Conversely, the treatment of HS with OLI, an inhibitor of oxidative phosphorylation, promotes GLUT-1 enhancement and a PKM2 dependent pro-inflammatory profile (not shown). Therefore, the evaluation of the immuno-metabolic profile could help to stratify NSTEMI patients and allow the identification of new therapeutic targets in the perspective of a personalized medicine approach [Created with BioRender.com]. ApoA1, apolipoprotein A1; CHI3L1, chitinase-3 like-1; FSN, fasentin; GLUT-1, glucose transporter 1; IL-6, interleukin 6; MPO, myeloperoxidase; PDGF, platelet-derived growth factor; PKM2, pyruvate kinase isozyme M2; RBP4, retinol-binding protein 4; SKN, shikonin.
Figure 1
Figure 1
GLUT-1 and PKM2 dependent glucose metabolism in CD4+ T cells and PBMCs. (A) GLUT-1 protein level and (B) glucose uptake in NSTEMI, CCS, and HS; (C) PKM2 mRNA expression and (D) PKM2 protein expression in NSTEMI and CCS patients. In (A), the data were described as mean ± standard deviation, based on their distribution. For intragroup analysis, we used one-way ANOVA with Tukey’s multiple comparison test. In (B), the data were described as median with interquartile range, based on their distribution. For intragroup analysis, we used one-way ANOVA nonparametric test, Kruskal–Wallis test with Dunn’s multiple comparison test. In (C) and (D), the data were described as median with interquartile range, based on their distribution. For comparisons between groups, we used the Mann–Whitney test. 2-NDG, 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose; GLUT-1, glucose transporter 1; MFI, median fluorescence intensity; PKM2, pyruvate kinase isozyme M2; PBMC, peripheral blood mononuclear cell.
Figure 2
Figure 2
Intracellular localization of PKM2 in NSTEMI, CCS, and HS. (A) Intra- and extra-nuclear PKM2 fluorescence (MFI) in NSTEMI, CCS, and H; (B) Representative immunofluorescence confocal images of PKM2 in PBMCs; PKM2 = red fluorescence, nuclei = DAPI; scale bar: 10 μm for all images. In (A), the data were described as median with interquartile range, based on their distribution. For intragroup analysis, we used one-way ANOVA nonparametric test, Kruskal–Wallis test with Dunn’s multiple comparison test. CCS, chronic coronary syndromes; (e), extra-nuclear; HS, healthy subject; (i), intra-nuclear; MFI, median fluorescence intensity; NSTEMI, non-ST-elevation myocardial infarction; PKM2, pyruvate kinase isozyme M2; PBMC, peripheral blood mononuclear cell.
Figure 3
Figure 3
Inhibition of GLUT-1/PKM2 metabolic loop by SKN and FSN in NSTEMI patients. (A) Representative immunofluorescence confocal images of PKM2 in the untreated PBMCs and treated with SKN or FSN PBMCs; PKM2 = red fluorescence, nuclei = DAPI; Scale bar: 10 μm for all images; (B) intra-nuclear PKM2 level in untreated and SKN-treated PBMCs (n = 8); (C) intra-nuclear PKM2 level in the untreated and FSN-treated PBMCs (n = 8); (D) GLUT-1 protein level in the untreated and SKN-treated PBMCs (n = 12); (E) GLUT-1 protein level in the untreated and FSN-treated PBMCs (n = 12); (F) inflammatory gene levels in UT-, SKN-, and FSN-treated PBMCs (n = 5). In B, C, D, E, and F (IL-6), for comparisons between groups, we used a paired t-test. In F (IL-1β and IFNγ), for comparisons between groups, we used a paired samples Wilcoxon test. FSN, fasentin; GLUT-1, glucose transporter 1; IFNγ, interferon gamma; IL-1β, interleukin 1 beta; IL-6, interleukin 6; NSTEMI, non-ST-elevation myocardial infarction; PKM2, pyruvate kinase isozyme M2; SKN, shikonin; UT, untreated.
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