Nrf2 attenuates the innate immune response after experimental myocardial infarction

Bromage, D. I.; Trevelin, S. C.; Huntington, J.; Yang, V.; Muthukumar, A.; Mackie, S.; Sawyer, G.; Zhang, X.; Santos, C.; Safinia, N.; Smyrnias, I.; Giacca, M.; Ivetic, A.; Shah, A.

doi:10.1101/2022.01.10.475615

bioRxiv · 10.1101/2022.01.10.475615

Nrf2 attenuates the innate immune response after experimental myocardial infarction

Bromage, D. I.·Trevelin, S. C.·Huntington, J.·Yang, V.·Muthukumar, A.·Mackie, S.·Sawyer, G.·Zhang, X.·Santos, C.·Safinia, N.·Smyrnias, I.·Giacca, M.·Ivetic, A.·Shah, A.

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Abstract

ObjectivesWe aimed to investigate the contribution of the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) to the inflammatory response after experimental myocardial infarction (MI). BackgroundThere is compelling evidence implicating dysregulated inflammation in the mechanism of ventricular remodeling and heart failure (HF) after MI. The transcription factor Nrf2 (encoded by Nfe2l2) is a promising target in this context. It impedes transcriptional upregulation of pro-inflammatory cytokines and is anti-inflammatory in various murine models. MethodsWe 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. ResultsFACS 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 inflammatory cytokines, chemokines, and their receptors, including IL6, Ccl2, and Cxcr4. RNA-seq analysis showed upregulated NRG expression in WT mice after MI compared to untreated mice, which was significantly higher in bioinformatically isolated CCR2+ cells. ConclusionsTaken together, the results suggest that Nrf2 signalling in leukocytes, and possibly CCR2+ monocyte-derived cardiac resident macrophages, may be potential targets to prevent post-MI ventricular remodeling.

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Bromage, D. I., Trevelin, S. C., Huntington, J., Yang, V., Muthukumar, A., Mackie, S., Sawyer, G., Zhang, X., Santos, C., Safinia, N., Smyrnias, I., Giacca, M., Ivetic, A., Shah, A.. 2022-01-10. Nrf2 attenuates the innate immune response after experimental myocardial infarction. https://doi.org/10.1101/2022.01.10.475615

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