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Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

Lookup NU author(s): Danlin Liu, Dr Gavin Richardson, Fehmi Benli, Dr Catherine Park, Joao Victor de De Souza Cunha, Dr Agnieszka Bronowska, Professor Ioakim Spyridopoulos

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Portland Press Ltd. , 2020.

For re-use rights please refer to the publisher's terms and conditions.


Abstract

In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets.It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities.In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.


Publication metadata

Author(s): Liu D, Richardson G, Benli FM, Park C, de Souza JV, Bronowska AK, Spyridopoulos I

Publication type: Article

Publication status: Published

Journal: Clinical Science

Year: 2020

Volume: 134

Issue: 17

Pages: 2243-2262

Online publication date: 03/09/2020

Acceptance date: 19/08/2020

Date deposited: 22/10/2020

ISSN (print): 0143-5221

ISSN (electronic): 1470-8736

Publisher: Portland Press Ltd.

URL: https://doi.org/10.1042/CS20191213

DOI: 10.1042/CS20191213


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