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Clearance of senescent cells during cardiac ischemia-reperfusion injury improves recovery

Lookup NU author(s): Emily Dookun, Dr Anna Walaszczyk, Dr Rachael Redgrave, Dr Pawel Palmowski, Dr Simon Tual-Chalot, Averina Suwana, Dr James Chapman, Leticia Donastorg Sosa, Oliver Yausep, Professor Ioakim Spyridopoulos, Professor Michael Taggart, Professor Helen Arthur, Dr Joao Passos, Dr Gavin Richardson

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


Abstract

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.


Publication metadata

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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