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Therapeutic potential of navitoclax in age-related cardiovascular diseases

Lookup NU author(s): Dr Anna Walaszczyk, Dr Emily Dookun, Dr Rachael Redgrave, Dr Pawel PalmowskiORCiD, Dr Simon Tual-Chalot, Dr Ellie Gill, Professor Ioakim SpyridopoulosORCiD, Professor Michael TaggartORCiD, Professor Helen ArthurORCiD, Dr Joao Passos, Dr Gavin RichardsonORCiD


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Cardiovascular disease (CVD) is the leading cause of death in individuals over 60 years old. Ageing is associated with decrease in myocardial function and a poorer prognosis following of myocardial infarction (MI). We have demonstrated that oxidative stress induced myocardial senescence contributes to both of these observations. In aged mice, prophylactic treatment with the senolytics drug navitoclax reduces senescence and the expression of SASP associated proteins, resulting in attenuated maladaptive myocardial remodelling and improved survival and functional outcome following MI. Furthermore, MI directly induces senescence and the SASP, as a result of increased oxidative stress, which are detrimental to outcome. In young animals, navitoclax treatment following MI with reperfusion improved left ventricular function, increased myocardial vascularisation, and decreased scar size. Proteomics revealed that elimination of senescent cells attenuated biological processes associated with maladaptive remodelling including fibrosis and inflammation. Cytokine array demonstrated navitoclax reduced expression of proinflammatory, profibrotic and anti‐angiogenic cytokines, including interferon gamma‐induced protein‐10, TGF‐β3, interleukin‐11, interleukin‐16 and fractalkine. Together our studies provide proof‐of‐concept evidence that cellular senescence and the proinflammatory SASP promote myocardial remodelling in multiple disease settings impairing heart function. Subsequently, senolytic treatment represents a potential novel therapeutic avenue to improve patient outcome for these CVDs.

Publication metadata

Author(s): Walaszczyk A, Dookun E, Redgrave R, Palmowski P, Tual Chalot S, Gill E, Owens A, Grieve D, Spyridopoulos I, Taggart M, Arthur H, Passos J, Richardson GD

Publication type: Conference Proceedings (inc. Abstract)

Publication status: Published

Conference Name: Termis 6th World Congress

Year of Conference: 2022

Pages: S395-S395

Online publication date: 04/04/2022

Acceptance date: 01/01/2022

ISSN: 1937-3341

Publisher: Mary Ann Liebert


DOI: 10.1089/ten.tea.2022.29025.abstracts

Library holdings: Search Newcastle University Library for this item

Series Title: Tissue Engineering Part A

ISBN: 1937335X