Endothelial dysfunction in acute myocardial infarction: cell-autonomous metabolic reprogramming and oxidative stress

  1. Erika Zodda
  2. Olga Tura-Ceide
  3. Nicholas L Mills
  4. Josep Tarragó-Celada
  5. Marina Carini
  6. Timothy M Thomson  Is a corresponding author
  7. Marta Cascante  Is a corresponding author
  1. University of Barcelona, Spain
  2. Dr Josep Trueta University Hospital de Girona, Spain
  3. University of Edinburgh, United Kingdom
  4. Università degli Studi di Milano, Italy
  5. Spanish National Research Council, Spain

Abstract

Background: Compelling evidence has accumulated on the role of oxidative stress on the endothelial cell (EC) dysfunction underlying acute coronary syndrome. However, unveiling the underlying metabolic determinants has been hampered by the scarcity of appropriate cell models to address cell-autonomous mechanisms of ED dysfunction.

Methods: We have generated endothelial cells derived from thrombectomy specimens from patients affected with acute myocardial infarction (AMI) and conducted phenotypical and metabolic characterization, focused on central carbon metabolism.

Results: AMI-derived endothelial cells (AMIECs), but not control healthy coronary endothelial cells, display impaired growth, migration and tubulogenesis. Metabolically, AMIECs displayed augmented reactive oxygen species (ROS) and glutathione intracellular content, along with a diminished glucose consumption coupled to high lactate production. Consistent with diminished glycolysis in AMIECs, the protein levels of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase type 3, PFKFB3, were downregulated. In contrast, PFKFB4 levels were upregulated, suggesting a shunting of glycolysis towards the pentose phosphate pathway (PPP), supported by upregulation in AMIECs of G6PD, the key enzyme in the oxidative branch of the PPP. Further, the glutaminolytic enzyme GLS was upregulated in AMIECs, providing a mechanistic explanation for the observed increase in glutathione content. Finally, AMIECs displayed a significantly higher mitochondrial membrane potential than control ECs, which, together with high ROS levels, suggest a highly coupled mitochondrial activity in patient ECs.

Conclusions: We suggest high mitochondrial proton coupling underlies the abnormally high production of ROS, balanced by PPP- and glutaminolysis-driven synthesis of glutathione, as a primary, cell-autonomous abnormality driving EC dysfunction in AMI.

Funding: European Commission Horizon 2020; CIBER- Carlos III National Institute of Health, Spain; Ministerio de Economia y Competitividad (MINECO) and Ministerio de Ciencia e Innovación, Spain; Generalitat de Catalunya-AGAUR, Catalonia; Plataforma Temática Interdisciplinar Salud Global (PTI-SG), Spain; British Heart Foundation, UK.

Data availability

All data generated or analysed during this study are included in the manuscript.

Article and author information

Author details

  1. Erika Zodda

    Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain
    Competing interests
    Erika Zodda, The European Commission Horizon 2020 research and innovation program under the MOGLYNET H2020-MSCAITNEJD grant (agreement No 675527): salary and research fundsGeneralitat de Catalunya-AGAUR: salary and research fundsPlataforma Temática Interdisciplinar - Salud Global: salary, travel expenses and research fundsMinisterio de Ciencia e Innovación, Spain: salary and research funds.
  2. Olga Tura-Ceide

    Department of Pulmonary Medicine, Dr Josep Trueta University Hospital de Girona, Girona, Spain
    Competing interests
    No competing interests declared.
  3. Nicholas L Mills

    BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    Nicholas L Mills, European Commission Horizon 2020 research and innovation program under the MOGLYNET H2020-MSCA-ITN-EJD grant: research funds.
  4. Josep Tarragó-Celada

    Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain
    Competing interests
    No competing interests declared.
  5. Marina Carini

    Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy
    Competing interests
    Marina Carini, European Commission Horizon 2020 research and innovation program under the MOGLYNET H2020-MSCA-ITN-EJD grant: research funds and travel expenses.
  6. Timothy M Thomson

    Institute for Molecular Biology of Barcelona, Spanish National Research Council, Barcelona, Spain
    For correspondence
    titbmc@ibmb.csic.es
    Competing interests
    Timothy M Thomson, CIBER- Carlos III National Institute of Health, Spain: research fundsMinisterio de Ciencia e Innovación, Spain: research fundsGeneralitat de Catalunya-AGAUR: research fundsPlataforma Temática Interdisciplinar - Salud Global: research funds.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4670-9440
  7. Marta Cascante

    Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain
    For correspondence
    martacascante@ub.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2062-4633

Funding

CIBER Carlos III National Institute of Health (CIBEREHD-CB17/04/00023)

  • Marina Carini
  • Timothy M Thomson

CIBER Carlos III National Institute of Health (CIBERES-CP17/00114)

  • Olga Tura-Ceide

Spanish Ministerio de Economia y Competitividad (PID2019-107139RB-C21)

  • Timothy M Thomson

Spanish Ministerio de Economia y Competitividad (PID2020-115051RB-I00)

  • Marina Carini

Generalitat de Catalunya-AGAUR (2021 SGR00350)

  • Marina Carini

Generalitat de Catalunya-AGAUR (2021 SGR1490)

  • Timothy M Thomson

Plataforma Temática Interdisciplinar - Salud Global (SGL2103019)

  • Timothy M Thomson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Edward D Janus, University of Melbourne, Australia

Ethics

Human subjects: Acute myocardial infection patient-derived endothelial cells (AMIECs) were isolated from coronary atherothrombotic specimens in patients undergoing percutaneous coronary intervention with thrombectomy for the treatment of acute ST-segment elevation myocardial infarction (STEMI) at the Royal Infirmary of Edinburgh, Scotland, UK. The study protocol was approved by the Institutional Research Ethics Committee, and all subjects provided written informed consent.

Version history

  1. Received: January 18, 2023
  2. Preprint posted: March 1, 2023 (view preprint)
  3. Accepted: August 1, 2023
  4. Accepted Manuscript published: November 28, 2023 (version 1)
  5. Version of Record published: February 16, 2024 (version 2)

Copyright

© 2023, Zodda et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Erika Zodda
  2. Olga Tura-Ceide
  3. Nicholas L Mills
  4. Josep Tarragó-Celada
  5. Marina Carini
  6. Timothy M Thomson
  7. Marta Cascante
(2023)
Endothelial dysfunction in acute myocardial infarction: cell-autonomous metabolic reprogramming and oxidative stress
eLife 12:e86260.
https://doi.org/10.7554/eLife.86260

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https://doi.org/10.7554/eLife.86260

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