# Modulation of Cardiac Gene Expression by anti-HMGB1 in a Model of Experimental Myocardial Infarction

## TL;DR

This study shows that blocking HMGB1 after a heart attack reduces inflammation and oxidative stress in rats, potentially offering a new treatment strategy.

## Contribution

The novel contribution is demonstrating that anti-HMGB1 treatment modulates cardiac gene expression and reduces post-MI injury in an experimental model.

## Key findings

- Anti-HMGB1 treatment reduced plasma TNFα and IL-6 levels after myocardial infarction.
- HMGB1 inhibition restored Nos3 gene expression and total NOS activity suppressed by MI.
- Antioxidant genes Sod1 and Sod2 were upregulated by anti-HMGB1, partially attenuating lipid peroxidation.

## Abstract

Myocardial infarction (MI) remains a major cause of morbidity and mortality. The ischemic myocardium undergoes necrosis and apoptosis, triggering inflammation and oxidative stress that drive fibrosis and heart failure. High-mobility group box 1 (HMGB1) protein acts as a key damage-associated molecular pattern, activating TLR4 and NFκB signaling to promote cytokine release and exacerbate injury. The present study investigated the role of HMGB1 in MI and its impact on inflammatory and redox-related pathways, focusing on the effects of HMGB1 blockade. Male WKY rats were divided into the following groups: sham, MI, and MI with anti-HMGB1 treatment (MI+aHMGB1). MI was induced in rats by coronary ligation followed by reperfusion, and the animals were evaluated seven days later. Plasma cytokines, total NOS activity and gene expression in the left ventricle were analyzed. MI significantly increased plasma TNFα and IL-6, while anti-HMGB1 treatment reduced both cytokines. Hmgb1 mRNA was markedly upregulated after MI and normalized by aHMGB1. MI suppressed Nos3 gene expression and total NOS activity, both of which were restored by aHMGB1. Tlr4 and NFκB mRNA levels were elevated after MI and remained high after HMGB1 inhibition, whereas Nos2 and IL-1β gene expression declined. Antioxidant responses showed differential regulation: Sod1 and Sod2 were further upregulated by aHMGB1, Gpx4 expression normalized, and lipid peroxidation was found to be partially attenuated. These findings indicate that HMGB1 is a key driver of post-infarction inflammation and oxidative injury. Its inhibition modulates cytokine production, restores redox balance, and enhances endothelial protection, suggesting a promising therapeutic target for limiting myocardial damage.