Abstract Body: Background: The role of reductive stress (RS) in regulating immune and inflammatory signaling in the heart remains poorly understood. We previously demonstrated that cardiac-specific expression of constitutively active Nrf2 (caNrf2) induces chronic RS, resulting in pathological cardiac remodeling. In the present study, we tested the hypothesis that sustained RS reprograms myocardial immune and inflammatory transcriptomes, thereby contributing to adverse cardiac remodeling.

Methods: NGS-based RNA-seq data from caNrf2-transgenic (TG) and non-transgenic (NTG) mouse hearts (6–8 months) were analyzed. Differential expression was assessed using DESeq2 (p<0.05; log2FC >0.5 or <-0.5). Functional enrichment was performed using DAVID Gene Ontology and MSigDB hallmark gene sets, and heatmaps were generated in R.

Results: Among 14,821 detected genes, 5,231 were significantly altered in TG hearts, of which 3,155 met criteria for substantial differential expression. Gene Ontology analysis identified 30 immune/inflammation-associated pathways involved in apoptosis, TNF signaling, NF-κB signaling, IFN-γ signaling, IL-1 signaling, IL-17 signaling, and leukocyte migration. Chronic RS broadly suppressed immune-inflammatory signaling in TG hearts. In apoptosis-related pathways, inhibitory/anti-apoptotic programs were predominantly downregulated, suggesting enhanced susceptibility to cell death. Similarly, genes involved in TNF, NF-κB, IFN-γ, IL-1, and IL-17 signaling, as well as leukocyte chemotaxis/migration, were largely downregulated relative to NTG hearts. Key altered genes included BCL2, CASP3, IRF1, NFKBIA, IL1R1, IL1R2, CXCL1, CCL2, CCL7, CSF1R, S100A8, and S100A9 suggesting compromised inflammatory signaling that may impair cardiac repair mechanisms.

Conclusions: Chronic Nrf2-driven reductive stress reprograms myocardial immune and inflammatory networks, characterized by suppression of cytokine signaling, impaired leukocyte recruitment, and enhanced susceptibility to apoptosis. These findings identify reductive stress as a critical regulator of immune homeostasis in the heart and suggest that RS-driven immune dysfunction contributes to pathological cardiac remodeling.