Patient Endothelial Colony-Forming Cells to Model Coronary Artery Disease Susceptibility and Unravel the Role of Dysregulated Mitochondrial Redox Signalling
Marie Besnier,
Meghan Finemore,
Christine Yu,
Katharine A. Kott,
Stephen T. Vernon,
Nicole A. Seebacher,
Elijah Genetzakis,
Anamarija Furman,
Owen Tang,
Ryan L. Davis,
Thomas Hansen,
Peter J. Psaltis,
Kristen J. Bubb,
Steven G. Wise,
Stuart M. Grieve,
Belinda A. Di Bartolo,
Gemma A. Figtree
Affiliations
Marie Besnier
Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Sydney, NSW 2006, Australia
Meghan Finemore
Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Sydney, NSW 2006, Australia
Christine Yu
Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Sydney, NSW 2006, Australia
Katharine A. Kott
Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Sydney, NSW 2006, Australia
Stephen T. Vernon
Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Sydney, NSW 2006, Australia
Nicole A. Seebacher
Department of Oncology, University of Oxford, Oxford OX1 2JD, UK
Elijah Genetzakis
Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Sydney, NSW 2006, Australia
Anamarija Furman
Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Sydney, NSW 2006, Australia
Owen Tang
Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Sydney, NSW 2006, Australia
Ryan L. Davis
Neurogenetics Group, Kolling Institute, St Leonards, NSW 2065, Australia
Thomas Hansen
Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Sydney, NSW 2006, Australia
Peter J. Psaltis
South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
Kristen J. Bubb
Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Sydney, NSW 2006, Australia
Steven G. Wise
School of Medical Sciences, Chronic Diseases Theme, University of Sydney, Sydngy, NSW 2006, Australia
Stuart M. Grieve
Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
Belinda A. Di Bartolo
Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Sydney, NSW 2006, Australia
Gemma A. Figtree
Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Sydney, NSW 2006, Australia
Mechanisms involved in the individual susceptibility to atherosclerotic coronary artery disease (CAD) beyond traditional risk factors are poorly understood. Here, we describe the utility of cultured patient-derived endothelial colony-forming cells (ECFCs) in examining novel mechanisms of CAD susceptibility, particularly the role of dysregulated redox signalling. ECFCs were selectively cultured from peripheral blood mononuclear cells from 828 patients from the BioHEART-CT cohort, each with corresponding demographic, clinical and CT coronary angiographic imaging data. Spontaneous growth occurred in 178 (21.5%) patients and was more common in patients with hypertension (OR 1.45 (95% CI 1.03–2.02), p = 0.031), and less likely in patients with obesity (OR 0.62 [95% CI 0.40–0.95], p = 0.027) or obstructive CAD (stenosis > 50%) (OR 0.60 [95% CI 0.38–0.95], p = 0.027). ECFCs from patients with CAD had higher mitochondrial production of superoxide (O2−–MitoSOX assay). The latter was strongly correlated with the severity of CAD as measured by either coronary artery calcium score (R2 = 0.46; p = 0.0051) or Gensini Score (R2 = 0.67; p = 0.0002). Patient-derived ECFCs were successfully cultured in 3D culture pulsatile mini-vessels. Patient-derived ECFCs can provide a novel resource for discovering mechanisms of CAD disease susceptibility, particularly in relation to mitochondrial redox signalling.
