Nrf2 attenuates the innate immune response after experimental myocardial infarction.

Autor: Bromage DI; School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK. Electronic address: daniel.bromage@kcl.ac.uk., Trevelin SC; School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK., Huntington J; School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK., Yang VX; School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK., Muthukumar A; School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK., Mackie SJ; School of Cancer and Pharmaceutical Sciences, SGDP Centre, King's College London, Memory Lane, London, SE5 8AF, UK., Sawyer G; School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK., Zhang X; School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK., Santos CXC; School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK., Safinia N; MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, King's College London, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK., Smyrnias I; School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK; School of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, Surrey, GU2 7AL, UK., Giacca M; School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK., Ivetic A; School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK., Shah AM; School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2022 May 28; Vol. 606, pp. 10-16. Date of Electronic Publication: 2022 Mar 19.
DOI: 10.1016/j.bbrc.2022.03.043
Abstrakt: Background: There is compelling evidence implicating dysregulated inflammation in the mechanism of ventricular remodeling and heart failure (HF) after MI. The transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2, encoded by Nfe2l2) is a promising target in this context since it impedes transcriptional upregulation of pro-inflammatory cytokines and is anti-inflammatory in various murine models.
Objectives: We aimed to investigate the contribution of Nrf2 to the inflammatory response after experimental myocardial infarction (MI).
Methods: We subjected Nrf2 -/- mice and wild type (WT) controls to permanent left coronary artery (LCA) ligation. The inflammatory response was investigated with fluorescence-activated cell sorting (FACS) analysis of peripheral blood and heart cell suspensions, together with qRT-PCR of infarcted tissue for chemokines and their receptors. To investigate whether Nrf2-mediated transcription is a dedicated function of leukocytes, we interrogated publicly available RNA-sequencing (RNA-seq) data from mouse hearts after permanent LCA ligation for Nrf2-regulated gene (NRG) expression.
Results: FACS analysis demonstrated a profoundly inflamed phenotype in the hearts of global Nrf2 -/- mice as compared to WT mice after MI. Moreover, infarcted tissue from Nrf2 -/- mice displayed higher expression of mRNA coding for inflammatory cytokines, chemokines, and their receptors, including IL-6, Ccl2, and Cxcr4. RNA-seq analysis showed upregulated NRG expression in WT mice after MI compared to naive mice, which was significantly higher in bioinformatically isolated CCR2 + cells.
Conclusions: Taken together, the results suggest that Nrf2 signalling in leukocytes, and possibly CCR2 + monocytes and monocyte-derived cardiac resident macrophages, may be potential targets to prevent post-MI ventricular remodeling.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Daniel Bromage reports financial support was provided by British Heart Foundation. Daniel Bromage reports financial support was provided by National Institute for Health Research. Daniel Bromage reports financial support was provided by Academy of Medical Sciences. Ajay Shah reports financial support was provided by British Heart Foundation. Mauro Giacca reports financial support was provided by British Heart Foundation. Mauro Giacca reports financial support was provided by European Research Council. Mauro Giacca reports a relationship with Trizell Holding SA that includes: board membership and consulting or advisory. Mauro Giacca reports a relationship with DINAQR AG that includes: board membership and consulting or advisory. Mauro Giacca reports a relationship with Purespring Therapeutics that includes: consulting or advisory and equity or stocks. Mauro Giacca reports a relationship with Forcefield Therapeutics that includes: consulting or advisory and equity or stocks. Ajay Shah reports a relationship with Forcefield Therapeutics that includes: board membership and consulting or advisory.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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