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

Autor:	Satta S; Department of Life Sciences, Manchester Metropolitan University, John Dalton Building, Chester Street, Manchester M1 5GD, UK.; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA., Beal R; Department of Life Sciences, Manchester Metropolitan University, John Dalton Building, Chester Street, Manchester M1 5GD, UK., Smith R; Department of Life Sciences, Manchester Metropolitan University, John Dalton Building, Chester Street, Manchester M1 5GD, UK., Luo X; Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, & The Key Laboratory of Medical Ischemia, Chinese Ministry of Education, Harbin 150086, China., Ferris GR; Department of Life Sciences, Manchester Metropolitan University, John Dalton Building, Chester Street, Manchester M1 5GD, UK., Langford-Smith A; Department of Life Sciences, Manchester Metropolitan University, John Dalton Building, Chester Street, Manchester M1 5GD, UK., Teasdale J; Bristol Medical School, Bristol Royal Infirmary, Upper Maudlin Street, Bristol BS2 8HW, UK., Ajime TT; Laboratory of Respiratory Diseases and Thoracic Surgery, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium., Serré J; Laboratory of Respiratory Diseases and Thoracic Surgery, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium., Hazell G; Bristol Medical School, Bristol Royal Infirmary, Upper Maudlin Street, Bristol BS2 8HW, UK., Newby GS; Bristol Medical School, Bristol Royal Infirmary, Upper Maudlin Street, Bristol BS2 8HW, UK., Johnson JL; Bristol Medical School, Bristol Royal Infirmary, Upper Maudlin Street, Bristol BS2 8HW, UK., Kurinna S; Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester M13 9PT, UK., Humphries MJ; Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester M13 9PT, UK., Gayan-Ramirez G; Laboratory of Respiratory Diseases and Thoracic Surgery, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium., Libby P; Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Degens H; Department of Life Sciences, Manchester Metropolitan University, John Dalton Building, Chester Street, Manchester M1 5GD, UK.; Institute of Sport Science and Innovations, Lithuanian Sports University, Sporto g. 6, LT-44221 Kaunas, Lithuania., Yu B; Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, & The Key Laboratory of Medical Ischemia, Chinese Ministry of Education, Harbin 150086, China., Johnson T; Department of Cardiology, Bristol Heart Institute, Upper Maudlin St., Bristol BS2 8HW, UK., Alexander Y; Department of Life Sciences, Manchester Metropolitan University, John Dalton Building, Chester Street, Manchester M1 5GD, UK., Jia H; Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, & The Key Laboratory of Medical Ischemia, Chinese Ministry of Education, Harbin 150086, China., Newby AC; Bristol Medical School, Bristol Royal Infirmary, Upper Maudlin Street, Bristol BS2 8HW, UK., White SJ; Department of Life Sciences, Manchester Metropolitan University, John Dalton Building, Chester Street, Manchester M1 5GD, UK.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 Aug 07; Vol. 119 (9), pp. 1869-1882.
DOI:	10.1093/cvr/cvad022
Abstrakt:	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 (TNFα) 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. Competing Interests: Conflict of interest: None of the authors have received any financial, personal, or professional support, other than the funding disclosed above that has a bearing on the data presented here. Dr Libby is an unpaid consultant to or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Norvo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron. Dr Libby is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, and XBiotech, Inc. Dr Libby’s laboratory has received research funding in the last 2 years from Novartis. Dr Libby is on the Board of Directors of XBiotech, Inc. Dr Libby has a financial interest in XBiotech, a company developing therapeutic human antibodies. Dr Libby has a financial interest in TenSixteen Bio, a company targeting somatic mosaicism and clonal haematopoiesis of indeterminate potential (CHIP) to discover and develop novel therapeutics to treat age-related diseases. Dr Libby’s interests were reviewed and managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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