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

Author:

Canonico Francesco1ORCID,Pedicino Daniela1ORCID,Severino Anna2,Vinci Ramona12ORCID,Flego Davide2,Pisano Eugenia1,d’Aiello Alessia2,Ciampi Pellegrino2,Ponzo Myriana2ORCID,Bonanni Alice12ORCID,De Ciutiis Astrid2,Russo Sara2,Di Sario Marianna2ORCID,Angelini Giulia12,Szczepaniak Piotr34,Baldi Alfonso5,Kapelak Boguslaw6,Wierzbicki Karol6,Montone Rocco A1ORCID,D’Amario Domenico1ORCID,Massetti Massimo12,Guzik Tomasz J34ORCID,Crea Filippo12ORCID,Liuzzo Giovanna12ORCID

Affiliation:

1. Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS , Largo A. Gemelli 8, 00168 Rome , Italy

2. Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart , Rome , Italy

3. Institute of Cardiovascular and Medical Sciences, University of Glasgow , Glasgow , UK

4. Department of Internal and Agricultural Medicine, Jagiellonian University, Collegium Medicum , Krakow , Poland

5. Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania ‘Luigi Vanvitelli’ , Caserta , Italy

6. Department of Cardiovascular Surgery and Transplantology, Jagiellonian University, John Paul II Hospital , Krakow , Poland

Abstract

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.

Funder

European Research Council

British Heart Foundation

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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