Sawyer, G. | bioRxiv Science

bioRxiv2022

Nrf2 attenuates the innate immune response after experimental myocardial infarction

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.

immunology↗

bioRxiv2021

Interplay between stress and reproduction: Novel epigenetic markers in response to shearing patterns in Australian Merino sheep (Ovis aries)

In this study, we determined the effect(s) of shearing on Australian Merino ewes (Ovis aries). To test this research question, we used a suite of field and laboratory methods including GPS collars, wool cortisol and novel epigenetic markers identified using Illumina NovaSeq RRBS. Single shorn ewes (n =24) kept on their full fleece throughout the entire gestation period while twice shorn ewes (n =24) had their wool shorn early in gestation. We have discovered one locus (Chr20:50404014) which was significantly associated with different shearing treatments (twice or single shorn ewes), (FDR = 0.005). This locus is upstream of a protein coding gene (ENSOARG00000002778.1), which shows similarities to the forkhead box C1 (FOXC1) mRNA using BLAST searches. We discovered that 36 gene loci were significantly modulated either between different shearing treatments or late vs early pregnancy ewes. Similarly, in lambs we identified 16 annotated gene loci that were significant between late vs early pregnancy. Early shorn ewes grazed 10% higher and maintained stronger body condition. Wool cortisol levels were significantly lower in the early shorn ewes during mid- and late gestation. Lambs bred from twice shorn ewes had on average better visual wool quality parameters in terms of micron, spin finesses and curvature. Collectively, this research provides a new dataset combining physiological, molecular epigenetics and digital tracking indices that advances our understanding of how Merino ewes respond to shearing frequency and this information could guide further research on sheep breeding and welfare. Significance StatementThis study provides novel data on the molecular epigenetic signatures in Merino sheep under exposure to natural environmental and management factors. We have discovered DNA methylation profiles from ewes and lambs that are directly associated with whole- animal physiology, development and growth. The baseline data can provide a useful resource for future research in many key areas such as animal welfare, diseases and climatic resilience that will benefit sheep and wool production.

genomics↗