Endothelial dysfunction in acute myocardial infarction: cell-autonomous metabolic reprogramming and oxidative stress
- University of Barcelona, Spain
- Dr Josep Trueta University Hospital de Girona, Spain
- University of Edinburgh, United Kingdom
- Università degli Studi di Milano, Italy
- 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
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.
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.
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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Endothelial dysfunction in acute myocardial infarction: cell-autonomous metabolic reprogramming and oxidative stress
eLife 12:e86260.
https://doi.org/10.7554/eLife.86260
Further reading
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Background:
Subarachnoid hemorrhage (SAH) is characterized by intense central inflammation, leading to substantial post-hemorrhagic complications such as vasospasm and delayed cerebral ischemia. Given the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation (taVNS) and its ability to promote brain plasticity, taVNS has emerged as a promising therapeutic option for SAH patients. However, the effects of taVNS on cardiovascular dynamics in critically ill patients, like those with SAH, have not yet been investigated. Given the association between cardiac complications and elevated risk of poor clinical outcomes after SAH, it is essential to characterize the cardiovascular effects of taVNS to ensure this approach is safe in this fragile population. Therefore, this study assessed the impact of both acute and repetitive taVNS on cardiovascular function.
Methods:
In this randomized clinical trial, 24 SAH patients were assigned to either a taVNS treatment or a sham treatment group. During their stay in the intensive care unit, we monitored patient electrocardiogram readings and vital signs. We compared long-term changes in heart rate, heart rate variability (HRV), QT interval, and blood pressure between the two groups. Additionally, we assessed the effects of acute taVNS by comparing cardiovascular metrics before, during, and after the intervention. We also explored acute cardiovascular biomarkers in patients exhibiting clinical improvement.
Results:
We found that repetitive taVNS did not significantly alter heart rate, QT interval, blood pressure, or intracranial pressure (ICP). However, repetitive taVNS increased overall HRV and parasympathetic activity compared to the sham treatment. The increase in parasympathetic activity was most pronounced from 2 to 4 days after initial treatment (Cohen’s d = 0.50). Acutely, taVNS increased heart rate, blood pressure, and peripheral perfusion index without affecting the corrected QT interval, ICP, or HRV. The acute post-treatment elevation in heart rate was more pronounced in patients who experienced a decrease of more than one point in their modified Rankin Score at the time of discharge.
Conclusions:
Our study found that taVNS treatment did not induce adverse cardiovascular effects, such as bradycardia or QT prolongation, supporting its development as a safe immunomodulatory treatment approach for SAH patients. The observed acute increase in heart rate after taVNS treatment may serve as a biomarker for SAH patients who could derive greater benefit from this treatment.
Funding:
The American Association of Neurological Surgeons (ALH), The Aneurysm and AVM Foundation (ALH), The National Institutes of Health R01-EB026439, P41-EB018783, U24-NS109103, R21-NS128307 (ECL, PB), McDonnell Center for Systems Neuroscience (ECL, PB), and Fondazione Neurone (PB).
Clinical trial number:
