TY - JOUR
T1 - A Nrf2-OSGIN1&2-HSP70 axis mediates cigarette smoke-induced endothelial detachment
T2 - Implications for plaque erosion
AU - Satta, Sandro
AU - Beal, Robert
AU - Smith, Rhys
AU - Luo, Xing
AU - Ferris, Glenn R.
AU - Langford-Smith, Alex
AU - Teasdale, Jack
AU - Ajime, Tom Tanjeko
AU - SerrCrossed D Sign©, Jef
AU - Hazell, Georgina
AU - Newby, Graciela Sala
AU - Johnson, Jason L.
AU - Kurinna, Svitlana
AU - Humphries, Martin J.
AU - Gayan-Ramirez, Ghislaine
AU - Libby, Peter
AU - Degens, Hans
AU - Yu, Bo
AU - Johnson, Thomas
AU - Alexander, Yvonne
AU - Jia, Haibo
AU - Newby, Andrew C.
AU - White, Stephen J.
N1 - Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2023/7/1
Y1 - 2023/7/1
N2 - 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.
AB - 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.
KW - adhesion
KW - Autophagy
KW - Endothelial erosion
KW - Nrf2
U2 - 10.1093/cvr/cvad022
DO - 10.1093/cvr/cvad022
M3 - Article
C2 - 36804807
AN - SCOPUS:85153098956
SN - 0008-6363
VL - 119
SP - 1869
EP - 1882
JO - Cardiovascular research
JF - Cardiovascular research
IS - 9
ER -
