PARP1 Inhibition and Effect on Burn Injury-Induced Inflammatory Response and Cardiac Function

Abstract

BACKGROUND: 

Burn injury induces multiple signaling pathways leading to a significant inflammatory storm that adversely affects multiple organs, including the heart. Poly (ADP-ribose) polymerase inhibitor 1 (PARP1) inhibition, with specific agents such as N-(5,6-Dihydro-6-oxo-2-phenanthridinyl)-2-acetamide (PJ34), is effective in reducing oxidative stress and cytokine expression in the heart. We hypothesized that PARP1 inhibition would reduce inflammatory signaling and protect against burn injury–induced cardiac dysfunction.

STUDY DESIGN: 

Male Sprague-Dawley rats (8 weeks old, 300 to 350 g) were randomly assigned to sham injury (Sham), 60% total body surface area burn (24 hours post burn), or 60% total body surface area burn with intraperitoneal administration of PJ34 (20 mg/kg, 24 hours post burn + PJ34) and sacrificed 24 hours after injury. Cardiac function was determined using Vevo 2100 echocardiography. Genetic expression of 84 specific toll-like receptor–mediated signal transduction and innate immunity genes were examined using microarray to evaluate cardiac tissue. Qiagen GeneGlobe Data Analysis Center was used to analyze expression, and genetic clustering was performed using TreeView V2.0.8 software. Real-time quantitative polymerase chain reaction was used to validate identified differentially expressed genes.

RESULTS: 

Burn injury significantly altered multiple genes in the toll-like receptor signaling, interleukin-17 signaling, tumor necrosis factor signaling, and nuclear factor-κB signaling pathways and led to significant cardiac dysfunction. PARP1 inhibition with PJ34 normalized these signaling pathways to sham levels as well as improved cardiac function to sham levels.

CONCLUSIONS: 

PARP1 inhibition normalizes multiple inflammatory pathways that are altered after burn injury and improves cardiac dysfunction. PARP1 pathway inhibition may provide a novel methodology to normalize multiple burn injury–induced inflammatory pathways in the heart.

In Brief

Poly (ADP-ribose) polymerase inhibitor 1 (PARP1) is a nuclear protein involved in repairing DNA single-stranded breaks. PARP1 inhibition reduces oxidative stress and cytokine expression in the heart, making it a novel therapeutic target after severe burn injury. We found that PARP1 inhibition improves cardiac function and normalizes the expression of inflammatory signaling pathways.