Abstract
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.
We aimed to investigate the contribution of Nrf2 to the inflammatory response after experimental myocardial infarction (MI).
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.
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.
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.
•Nrf2 is a promising target for treating dysregulated inflammation after myocardial infarction (MI).•Nrf2-/- mice demonstrated a profoundly inflamed cardiac phenotype as compared to WT mice after MI.•Nrf2-regulated genes (NRG) were up-regulated in leukocytes after MI, indicating a central role in the inflammatory response.•NRG expression was higher in CCR2+ cells, suggesting Nrf2 is important in monocytes and monocyte-derived macrophages.