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Lookup NU author(s): Emily Dookun, Dr Anna Walaszczyk, Dr Rachael Redgrave, Dr Pawel Palmowski, Dr Simon Tual-Chalot, Averina Suwana, Dr James ChapmanORCiD, Leticia Donastorg Sosa, Oliver Yausep, Professor Ioakim SpyridopoulosORCiD, Professor Michael Taggart, Professor Helen ArthurORCiD, Dr Joao Passos, Dr Gavin RichardsonORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
A key component of cardiac ischemia–reperfusion injury (IRI) is the increased generation of reactive oxygen species, leading to enhanced inflammation and tissue dysfunction in patients following intervention for myocardial infarction. In this study, we hypothesized that oxidative stress, due to ischemia–reperfusion, induces senescence which contributes to the pathophysiology of cardiac IRI. We demonstrate that IRI induces cellular senescence in both cardiomyocytes and interstitial cell populations and treatment with the senolytic drug navitoclax after ischemia–reperfusion improves left ventricular function, increases myocardial vascularization, and decreases scar size. SWATH‐MS‐based proteomics revealed that biological processes associated with fibrosis and inflammation that were increased following ischemia–reperfusion were attenuated upon senescent cell clearance. Furthermore, navitoclax treatment reduced the expression of pro‐inflammatory, profibrotic, and anti‐angiogenic cytokines, including interferon gamma‐induced protein‐10, TGF‐β3, interleukin‐11, interleukin‐16, and fractalkine. Our study provides proof‐of‐concept evidence that cellular senescence contributes to impaired heart function and adverse remodeling following cardiac ischemia–reperfusion. We also establish that post‐IRI the SASP plays a considerable role in the inflammatory response. Subsequently, senolytic treatment, at a clinically feasible time‐point, attenuates multiple components of this response and improves clinically important parameters. Thus, cellular senescence represents a potential novel therapeutic avenue to improve patient outcomes following cardiac ischemia–reperfusion.
Author(s): Dookun E, Walaszczyk A, Redgrave R, Palmowski P, Tual Chalot S, Suwana A, Chapman J, Jirkovsky E, Donastorg Sosa L, Gill E, Yausep O, Santin Y, Mialet Perez J, Owens WA, Grieve D, Spyridopoulos I, Taggart M, Arthur HM, Passos JF, Richardson GD
Publication type: Article
Publication status: Published
Journal: Aging Cell
Year: 2020
Volume: 19
Issue: 10
Print publication date: 29/09/2020
Online publication date: 29/09/2020
Acceptance date: 03/09/2018
Date deposited: 06/11/2020
ISSN (print): 1474-9718
ISSN (electronic): 1474-9726
Publisher: Wiley
URL: https://doi.org/10.1111/acel.13249
DOI: 10.1111/acel.13249
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