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

Emily Dookun, Anna Walaszczyk, Rachael Redgrave, Pawel Palmowski, Simon Tual-Chalot, Averina Suwana, James Chapman, Eduard Jirkovsky, Leticia Donastorg Sosa, Eleanor Gill, Oliver E. Yausep, Yohan Santin, Jeanne Mialet-Perez, W. Andrew Owens, David Grieve, Ioakim Spyridopoulos, Michael Taggart, Helen M. Arthur, João F. Passos, Gavin D. Richardson

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article numbere13249
JournalAging Cell
Volume19
Issue number10
DOIs
StatePublished - Oct 1 2020

Keywords

  • cardiac
  • ischemia–reperfusion
  • remodeling
  • senescence
  • senolytic

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Fingerprint Dive into the research topics of 'Clearance of senescent cells during cardiac ischemia–reperfusion injury improves recovery'. Together they form a unique fingerprint.

Cite this