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

Abstract

AIM:

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 (HS). NSTEMI patients showed higher expression of GLUT-1 and an enhanced glucose uptake in T cells as compared to CCS patients (p < 0.0001; p = 0.0101, respectively) and HS (p = 0.0071; p = 0.0122, respectively). PKM2 had a prevalent nuclear localization in T lymphocytes in NSTEMI (p = 0.0005 for nuclear versus cytoplasm localization), while in CCS and HS was equally distributed in both compartments. In addition, the nuclear fraction of PKM2 was significantly higher in NSTEMI compared to 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 downregulation of pro-inflammatory cytokine expression.

CONCLUSIONS:

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.

• Authors: Francesco Canonico, Daniela Pedicino, Anna Severino, Ramona Vinci, Davide Flego, Eugenia Pisano, Alessia d'Aiello, Pellegrino Ciampi, Myriana Ponzo, Alice Bonanni, Astrid De Ciutiis, Sara Russo, Marianna Di Sario, Giulia Angelini, Piotr Szczepaniak, Alfonso Baldi, Boguslaw Kapelak, Karol Wierzbicki, Rocco A Montone, Domenico D'Amario, Massimo Massetti, Tomasz J Guzik, Filippo Crea, Giovanna Liuzzo
• Journal: Cardiovascular research (Cardiovasc Res) (Dec 13 2022) ISSN: 1755-3245 [Electronic] England
• PMID: 36508576 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected].