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

E. Dookun, A. Walaszczyk, R. Redgrave, P. Palmowski, S. Tual-Chalot, A. Suwana, J. Chapman, E. Jirkovsky, L. Donastorg Sosa, E. Gill, OE. Yausep, Y. Santin, J. Mialet-Perez, W. Andrew Owens, D. Grieve, I. Spyridopoulos, M. Taggart, HM. Arthur,...

. 2020 ; 19 (10) : e13249. [pub] 20200929

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc21026494

Grantová podpora
PG/18/57/33941 British Heart Foundation - United Kingdom
PG/19/15/34269 British Heart Foundation - United Kingdom
Wellcome Trust - United Kingdom
PG/18/25/33587 British Heart Foundation - United Kingdom
PG/14/86/31177 British Heart Foundation - United Kingdom
PG/15/18/31333 British Heart Foundation - United Kingdom

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.

Citace poskytuje Crossref.org

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