Disruption of the novel nested gene mediates disturbed flow-induced atherosclerosis in mice.

Disturbed shear stress-induced endothelial atherogenic responses are pivotal in the initiation and progression of atherosclerosis, contributing to the uneven distribution of atherosclerotic lesions. This study investigates the role of , a novel nested gene variant, in disturbed flow-induced endothelial cell activation and atherosclerosis. We demonstrate that disturbed shear stress significantly reduces expression in athero-prone regions. Using three distinct mouse models with manipulated expression, we demonstrate that exerts potent anti-inflammatory and anti-atherosclerotic effects in mice. RNA sequencing revealed that interferon regulatory factor 5 (), a key regulator of inflammatory processes, mediates inflammatory responses associated with deficiency. interacts with , promoting its retention in the cytoplasm, thereby inhibiting the -dependent inflammatory pathways. Notably, knockdown in deficient mice almost completely rescues the aggravated atherosclerotic phenotype. Moreover, endothelial-specific supplementation using the CRISPR/Cas9 system significantly ameliorated endothelial activation and atherosclerosis. These findings elucidate a novel role for in mitigating endothelial inflammation and atherosclerosis by acting as an inhibitor of , highlighting its potential as a valuable therapeutic approach for treating atherosclerosis.