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A Nrf2-OSGIN1&2-HSP70 axis mediates cigarette smoke-induced endothelial detachment: Implications for plaque erosion

Lookup NU author(s): Dr Stephen WhiteORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology. Aims: Endothelial erosion of plaques is responsible for ∼30% of acute coronary syndromes (ACS). Smoking is a risk factor for plaque erosion, which most frequently occurs on the upstream surface of plaques where the endothelium experiences elevated shear stress. We sought to recreate these conditions in vitro to identify potential pathological mechanisms that might be of relevance to plaque erosion. Methods and results: Culturing human coronary artery endothelial cells (HCAECs) under elevated flow (shear stress of 7.5 Pa) and chronically exposing them to cigarette smoke extract (CSE) and tumour necrosis factor-Alpha (TNF) recapitulated a defect in HCAEC adhesion, which corresponded with augmented Nrf2-regulated gene expression. Pharmacological activation or adenoviral overexpression of Nrf2 triggered endothelial detachment, identifying Nrf2 as a mediator of endothelial detachment. Growth/Differentiation Factor-15 (GDF15) expression was elevated in this model, with protein expression elevated in the plasma of patients experiencing plaque erosion compared with plaque rupture. The expression of two Nrf2-regulated genes, OSGIN1 and OSGIN2, was increased by CSE and TNFα under elevated flow and was also elevated in the aortas of mice exposed to cigarette smoke in vivo. Knockdown of OSGIN1&2 inhibited Nrf2-induced cell detachment. Overexpression of OSGIN1&2 induced endothelial detachment and resulted in cell cycle arrest, induction of senescence, loss of focal adhesions and actin stress fibres, and disturbed proteostasis mediated in part by HSP70, restoration of which reduced HCAEC detachment. In ACS patients who smoked, blood concentrations of HSP70 were elevated in plaque erosion compared with plaque rupture. Conclusion: We identified a novel Nrf2-OSGIN1&2-HSP70 axis that regulates endothelial adhesion, elevated GDF15 and HSP70 as biomarkers for plaque erosion in patients who smoke, and two therapeutic targets that offer the potential for reducing the risk of plaque erosion.

Publication metadata

Author(s): Satta S, Beal R, Smith R, Luo X, Ferris GR, Langford-Smith A, Teasdale J, Ajime TT, SerrCrossed D SignCopyright J, Hazell G, Newby GS, Johnson JL, Kurinna S, Humphries MJ, Gayan-Ramirez G, Libby P, Degens H, Yu B, Johnson T, Alexander Y, Jia H, Newby AC, White SJ

Publication type: Article

Publication status: Published

Journal: Cardiovascular Research

Year: 2023

Volume: 119

Issue: 9

Pages: 1869-1882

Print publication date: 01/07/2023

Online publication date: 18/02/2023

Acceptance date: 05/01/2023

Date deposited: 08/11/2023

ISSN (print): 0008-6363

ISSN (electronic): 1755-3245

Publisher: Oxford University Press


DOI: 10.1093/cvr/cvad022

PubMed id: 36804807


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Funder referenceFunder name
American Heart Association
British Heart Foundation
European Commission
National Health Research Institute (UK) Bristol Biomedical Research Unit in Cardiovascular Medicine
Manchester Metropolitan University
RRM Charitable Fund
Simard Fund
US National Heart, Lung, and Blood Institute