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The senescence-associated secretory phenotype as a biomarker for age-related myocardial remodelling and cardiovascular disease

Lookup NU author(s): Dr Rachael Redgrave, Dr Maria Camacho EncinaORCiD, Dr Simon Tual-ChalotORCiD, Dr Omowumi Folaranmi, Dr Carmen Martin-RuizORCiD, Professor Ioakim SpyridopoulosORCiD, Dr Jason GillORCiD, Professor Gavin RichardsonORCiD

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Abstract

Introduction Preclinical models have demonstrated that the accumulation of senescent myocardial cells is casual to age-related myocardial dysfunction. In vitro and in vivo studies point to the pro-inflammatory senescence-associated secretory phenotype (SASP) being a key driver of cardiac remodelling, but this is decidedly more well-studied in the murine context. The role of SASP in myocardial remodelling clinically, and the capacity of the human myocardial SASP to serve as a biomarker for age-related cardiac remodelling and associated CVD, is still unclear. We aimed to evaluate this by marrying in vitro studies with clinical data from a large, older (> 85 years-old) patient cohort, and clinical data from small cohort of human donor hearts spanning a range of normality.Methods and Results In human donor hearts, left ventricular p16 protein expression correlated with donor age (Pearson’s correlation=0.631, p<0.1), indicating that senescence is associated with increased donor age. To identify the mechanisms by which myocardial senescence may drive age-related dysfunction, we employed an in vitro model. AC16 cardiomyocytes were induced to senescence using doxorubicin (shown by transcript- and protein-level induction of classical senescence markers p16 (figure 1A) and p21), demonstrating the utility of this in vitro model for recapitulating cardiac senescence. Suggesting that cardiomyocyte senescence contributes to clinical age-related cardiac dysfunction through paracrine mechanisms, senescent human cardiomyocytes expressed a functional SASP which induced phenotypic changes in cardiac fibroblasts (formation of smooth muscle actin-positive stress fibres). Subsequent molecular analysis identified that this SASP contained emergent biomarkers of clinical CVD including GDF15 (figure 1B) and fractalkine. Fractalkine has previously been associated with poorer outcomes in clinical CVD but GDF15 is currently not well-understood. Therefore, GDF15 was analysed in clinical data from a large, older patient cohort (Newcastle 85+ study, n = 774) and was found to significantly elevated in patients with cardiac dysfunction (figure 2A, p<0.005), alongside the gold-standard clinical biomarker of cardiac dysfunction, NT-proBNP (figure 2B). Conclusions Cardiomyocyte senescence is associated with a functional SASP which is capable of inducing remodelling phenotypes in non-cardiomyocyte cell types. Selected SASP factors such as GDF15 appear to show utility as clinical biomarkers of an aged, diseased cardiac phenotype. These may be useful additions to current biomarkers to form a signature which may aid prognosis and monitoring of CVD, even outside an ageing context.


Publication metadata

Author(s): Booth L, Redgrave R, Camacho Encina M, Tual-Chalot S, Folaranmi O, Martin-Ruiz C, Spyridopoulos I, Gill J, Richardson GD

Publication type: Article

Publication status: Published

Journal: Heart

Year: 2023

Volume: 109

Issue: Supp. 3

Pages: A265-A266

Print publication date: 05/06/2023

Online publication date: 02/06/2023

Acceptance date: 02/06/2023

ISSN (print): 1355-6037

ISSN (electronic): 1468-201X

Publisher: BMJ Publishing Group

URL: http://dx.doi.org/10.1136/heartjnl-2023-BCS.244

DOI: 10.1136/heartjnl-2023-BCS.244


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