Neutrophil Extracellular Traps Induce Abdominal Aortic Aneurysm Formation by Promoting the Synthetic and Proinflammatory Smooth Muscle Cell Phenotype via Hippo-YAP Pathway

The neutrophil plays an important role during abdominal aortic aneurysm (AAA) formation by undergoing histone citrullination with peptidyl arginine deiminase 4 (encoded by Padi4) and releasing neutrophil extracellular traps (NETs). However, the specific role of NETs during AAA formation is elusive. We found the levels of NET components in serum and tissues were found to be significantly associated with the clinical outcome of AAA patients. Furthermore, we reported that NETs induced the synthetic and proinflammatory smooth muscle cells (SMCs) phenotype and promoted AAA formation in a Hippo-YAP pathway-dependent manner by in vitro and in vivo experiments. Padi4 or YAP global knockout mice, exhibited significantly less synthetic and proinflammatory phenotypes of SMCs and developed AAA with lower frequency and severity compared with those of controls. Further studies indicated that the phenotypic switch of SMCs was associated with NETs-regulated enrichment status of H3K4me3 and H3K27me3 at promoters of synthetic and proinflammatory genes in SMCs. Cumulatively, these data suggest that NETs contribute to AAA formation by promoting the synthetic and proinflammatory phenotype of SMCs via inhibiting the Hippo-YAP pathway. A better understanding of the molecular mechanisms that regulate NETs and SMC phenotype is important to provide suitable cellular targets to prevent AAA.

Abdominal aortic aneurysm; Hippo pathway; Neutrophil extracellular traps; Phenotypic transition; Smooth muscle cells.