DNA-PKcs Phosphorylates Cofilin2 to Induce Endothelial Dysfunction and Microcirculatory Disorder in Endotoxemic Cardiomyopathy
RESEARCH(2024)
Abstract
The presence of endotoxemia is strongly linked to the development of endothelial dysfunction and disruption of myocardial microvascular reactivity. These factors play a crucial role in the progression of endotoxemic cardiomyopathy. Sepsis -related multiorgan damage involves the participation of the catalytic subunit of DNA -dependent protein kinase (DNA-PKcs). However, whether DNA-PKcs contributes to endothelial dysfunction and myocardial microvascular dysfunction during endotoxemia remains unclear. Hence, we conducted experiments in mice subjected to lipopolysaccharide (LPS)-induced endotoxemic cardiomyopathy, as well as assays in primary mouse cardiac microvascular endothelial cells. Results showed that endothelial -cell -specific DNA-PKcs ablation markedly attenuated DNA damage, sustained microvessel perfusion, improved endothelial barrier function, inhibited capillary inflammation, restored endothelium -dependent vasodilation, and improved heart function under endotoxemic conditions. Furthermore, we show that upon LPS stress, DNA-PKcs recognizes a TQ motif in cofilin2 and consequently induces its phosphorylation at Thr 25 . Phosphorylated cofilin2 shows increased affinity for F -actin and promotes F -actin depolymerization, resulting into disruption of the endothelial barrier integrity, microvascular inflammation, and defective eNOS-dependent vasodilation. Accordingly, cofilin2-knockin mice expressing a phospho-defective (T25A) cofilin2 mutant protein showed improved endothelial integrity and myocardial microvascular function upon induction of endotoxemic cardiomyopathy. These findings highlight a novel mechanism whereby DNA-PKcs mediates cofilin2 Thr25 phosphorylation and subsequent F -actin depolymerization to contribute to endotoxemia-related cardiac microvascular dysfunction.
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