OC 68.3 - Understanding the role of the renin-angiotensin system in endothelial senescence in chronic obstructive pulmonary disease

Tuesday, July 12, 2022

3:15 PM – 3:30 PM

Location: ExCel Center, ICC Capital Suite Room 17

Presentation Format: In-Person

Presenting Author(s)

Koralia Paschalaki, MD, PhD

Respiratory physician - Clinical Research Fellow
National Heart and Lung Institute, Imperial College London
London, England, United Kingdom

Co-Author(s)

DG

Daisy Gresham

Research Technician
National Heart and Lung Institute, Imperial College London
London, England, United Kingdom
CP

Charis Pericleous

Research Fellow
National Heart and Lung Institute, Imperial College London
London, England, United Kingdom
MM

Mairi MacLeod

Clinical Research Fellow
National Heart and Lung Institute, Imperial College London
London, England, United Kingdom
GD

Gavin Donaldson

Professor of Respiratory Studies
National Heart and Lung Institute, Imperial College London
London, England, United Kingdom
JW

Jadwiga Wedzicha

Professor of Respiratory Medicine
National Heart and Lung Institute, Imperial College London
London, England, United Kingdom
JM

Justin C. Mason

Professor of Vascular Rheumatology
National Heart and Lung Institute, Imperial College London
London, England, United Kingdom
PB

Peter Barnes

Professor of Thoracic Medicine
National Heart and Lung Institute, Imperial College London
London, England, United Kingdom
Anna M. Randi, MD,PhD

Professor of Cardiovascular Medicine
Imperial College London
London, England, United Kingdom

Background: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Endothelial senescence promotes vascular ageing and atherosclerosis. Endothelial-colony-forming-cells (ECFC), provide non-invasive access to endothelial cells in patients. The renin-angiotensin system (RAS) and particularly Angiotensin(Ang)-II are implicated in COPD pathogenesis and in CVD.

Aims: To investigate the role of AngII in endothelial senescence and vascular ageing in COPD, and test possible pharmacological interventions.

Methods: ECFC were isolated and expanded from peripheral blood samples of healthy non-smokers, healthy smokers and COPD patients. Senescence was measured by senescence-associated-β-galactosidase (SA-β-Gal) activity. Additional markers of senescence (p16, p21), DNA damage (γ-H2AX, 53BP1) and selective senescence associated secretory phenotype (SASP) mediators were measured by immunofluorescence confocal microscopy. We use a high-throughput ‘organ-on-a-chip’ microfluidic platform (OrganoPlate, MIMETAS Netherlands) that allows the long-term culture of endothelial cells and formation of microvessels for functional and immunofluorescent analysis.

Results: We have previously demonstrated in ECFC from COPD patients increased DNA damage response (DDR), ataxia-telangiectasia-mutated (ATM) activation and endothelial senescence due to epigenetic dysfunction involving the histone deacetylase sirtuin(SIRT)-1, supporting the concept of accelerated endothelial ageing as a contributor to CVD in COPD. We now show that ECFC senescence is accompanied by a proinflammatory phenotype (increased IFN-γ-inducible-protein-10) in a subgroup of COPD patients not receiving treatment with inhaled-corticosteroids. We have optimised in vitro 2D and 3D models of premature endothelial senescence caused by AngII. Pharmacological treatment with SIRT1 activators, ATM inhibitors, and AngII receptor blockers could inhibit the increased senescence in ECFC from COPD patients.

Conclusion(s): We demonstrate that ECFC from patients with COPD exhibit increased senescence possibly due to aberrant activation of the RAS system and could be amenable to treatment. These defects may contribute to endothelial dysfunction and CVD in COPD and could potentially constitute therapeutic targets for intervention.