Key Protein Worsens Sepsis-Induced Heart Damage by Disrupting Protective Pathway

Sepsis, a life-threatening response to infection, often leads to myocardial microvascular injury, causing severe heart dysfunction and increasing mortality. The precise mechanisms by which this damage occurs are not fully understood, making effective treatments challenging. This study specifically investigates how the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) contributes to endotoxemia-induced myocardial injury and its interaction with protective cellular pathways.

The study revealed that activation of DNA-PKcs significantly exacerbated myocardial microvascular injury in endotoxemic mice, leading to impaired cardiac function. Treatment with the DNA-PKcs inhibitor NU7441 resulted in a 45% reduction in microvascular leakage and a 30% improvement in left ventricular ejection fraction compared to untreated endotoxemic controls (p<0.01). They found that DNA-PKcs disrupts the protective MOTS-c/JNK pathway, leading to increased inflammation and cell death. > Administration of MOTS-c significantly attenuated the injury, restoring cardiac function by 28% and reducing inflammatory markers by 35% in endotoxemic mice (p<0.001). This protective effect was linked to MOTS-c's ability to suppress JNK activation and prevent profilin-mediated lamellipodia degradation, which is crucial for endothelial cell integrity.