Abstract Body: Background
Sepsis is our body’s immune response against any infection, resulting in multiple organ failure and death if not treated promptly. Increased oxidative stress and inflammation are key factors in myocardial dysfunction, characterized by acute ventricular failure, dilated ventricles, and reduced ejection fraction and fractional shortening. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays an important role in maintaining cellular redox homeostasis by regulating the expression of various antioxidant and cryoprotective genes. However, the role of NRF2 in septic cardiomyocytes is not well understood.
Methods and Results
Transgenic mice that overexpress cardiac-specific NRF2 (TG-CaNRF2), along with their control littermates (NTG), were injected intraperitoneally cecal slurry (CS). We monitored the mice's cardiac function and survival, and after 24 hours, we collected cardiac tissues to analyze the expression of NRF2, its downstream target genes, and inflammation using qPCR. We observed increased myocardial expression of NRF2 mRNA and its downstream target, glutathione reductase (GSR), compared to non-transgenic littermates (NTG). Following cecal-slurry (CS) injection, Kaplan-meier curve showed that 80% of TG mice survived after 24 hours, whereas survival in NTG mice dropped below 40% (P < 0.05). Echocardiography revealed that NTG hearts had a significant decline in ejection fraction (EF) and fractional shortening (FS) 12 hours post-CS, while TG hearts maintained contractile function and were improved, similar to NTG controls. Pro-inflammatory cytokines IL-6 and IL-1β increased sharply in NTG mice but were suppressed in TG hearts.

Conclusion
These results demonstrate that enhancing NRF2-related antioxidant capacity reduces inflammation, preserves heart function, and significantly improves survival in septic mice, supporting the idea that redox-targeted therapies could help mitigate septic cardiomyopathy.