Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain; Institute for Molecular Biology of Barcelona, National Research Council (IBMB-CSIC), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-EDH), Madrid, Spain
Olga Tura-Ceide
Department of Pulmonary Medicine, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS); University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain; Department of Pulmonary Medicine, Dr. Josep Trueta University Hospital de Girona, Santa Caterina Hospital de Salt and Girona Biomedical Research Institute (IDIBGI), Girona, Spain
Nicholas L Mills
University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
Josep Tarragó-Celada
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain
Marina Carini
Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy
Institute for Molecular Biology of Barcelona, National Research Council (IBMB-CSIC), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-EDH), Madrid, Spain; Universidad Peruana Cayetano Heredia, Lima, Peru
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-EDH), Madrid, Spain; Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain
Compelling evidence has accumulated on the role of oxidative stress on the endothelial cell (EC) dysfunction in acute coronary syndrome. Unveiling the underlying metabolic determinants has been hampered by the scarcity of appropriate cell models to address cell-autonomous mechanisms of EC dysfunction. We have generated endothelial cells derived from thrombectomy specimens from patients affected with acute myocardial infarction (AMI) and conducted phenotypical and metabolic characterizations. AMI-derived endothelial cells (AMIECs) display impaired growth, migration, and tubulogenesis. Metabolically, AMIECs displayed augmented ROS and glutathione intracellular content, with a diminished glucose consumption coupled to high lactate production. In AMIECs, while PFKFB3 protein levels of were downregulated, PFKFB4 levels were upregulated, suggesting a shunting of glycolysis towards the pentose phosphate pathway, supported by upregulation of G6PD. Furthermore, the glutaminolytic enzyme GLS was upregulated in AMIECs, providing an explanation for the increase in glutathione content. Finally, AMIECs displayed a significantly higher mitochondrial membrane potential than control ECs, which, together with high ROS levels, suggests a coupled mitochondrial activity. We suggest that high mitochondrial proton coupling underlies the high production of ROS, balanced by PPP- and glutaminolysis-driven synthesis of glutathione, as a primary, cell-autonomous abnormality driving EC dysfunction in AMI.
