Nrf2 attenuates the innate immune response after experimental myocardial infarction

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.