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

doi:10.3390/antiox10101547

Patient Endothelial Colony-Forming Cells to Model Coronary Artery Disease Susceptibility and Unravel the Role of Dysregulated Mitochondrial Redox Signalling

Antioxidants (Basel). 2021 Sep 29;10(10):1547. doi: 10.3390/antiox10101547.

Authors

Marie Besnier¹, Meghan Finemore¹, Christine Yu¹, Katharine A Kott^{1

2}, Stephen T Vernon^{1

2}, Nicole A Seebacher³, Elijah Genetzakis¹, Anamarija Furman¹, Owen Tang¹, Ryan L Davis^{4

5}, Thomas Hansen^{1

2}, Peter J Psaltis^{6

7}, Kristen J Bubb^{1

8}, Steven G Wise^{9

10}, Stuart M Grieve^{5

11

12}, Belinda A Di Bartolo¹, Gemma A Figtree^{1

2

10

13}

Affiliations

¹ Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Sydney, NSW 2006, Australia.
² Department of Cardiology, Royal North Shore Hospital, Sydney, NSW 2065, Australia.
³ Department of Oncology, University of Oxford, Oxford OX1 2JD, UK.
⁴ Neurogenetics Group, Kolling Institute, St Leonards, NSW 2065, Australia.
⁵ Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia.
⁶ South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia.
⁷ Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia.
⁸ Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
⁹ School of Medical Sciences, Chronic Diseases Theme, University of Sydney, Sydngy, NSW 2006, Australia.
¹⁰ Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia.
¹¹ Charles Perkins Centre, Sydney Translational Imaging Laboratory, University of Sydney, Sydney, NSW 2006, Australia.
¹² Department of Radiology, Royal Prince Alfred Hospital, Camperdown, Sydney, NSW 2050, Australia.
¹³ Cardiothoracic and Vascular Health, Kolling Institute of Medical Research, 10 Westbourne Street, St Leonards, NSW 2065, Australia.

Abstract

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.

Keywords: atherosclerosis; biomarkers; coronary artery disease; endothelial cells; risk factors.