Low-Shear Stress Promotes Atherosclerosis via Inducing Endothelial Cell Pyroptosis Mediated by IKKε/STAT1/NLRP3 Pathway
Yifei Lv, Zihao Jiang, Wenying Zhou, Hongfeng Yang, Guozhen Jin, Dongchen Wang, Chaohua Kong, Zhiyuan Qian, Yue Gu, Shaoliang Chen, Linlin Zhu
Abstract
Abstract Atherosclerosis is initiated by vascular endothelial dysfunction, and low-shear stress (LSS) of blood flow is a key factor leading to endothelial dysfunction. Growing evidence suggests that endothelial cell pyroptosis plays an important role in the development of atherosclerosis. Studies have shown that low-shear stress can induce endothelial cell pyroptosis, but the exact mechanism remains unclear. Our experiments demonstrated that low-shear stress induced endothelial cell pyroptosis and the phosphorylation of IκB kinase ε (IKKε). IKKε knockdown not only significantly attenuated atherosclerosis lesions of aortic arch areas in ApoE −/− mice fed with high cholesterol diets, but also markedly reduced endothelial cell pyroptosis and NLRP3 expression triggered by low-shear stress. Further mechanism studies showed that IKKε promoted the expression of NLRP3 via activating signal transducer and activator of transcription 1 (STAT1) and the subsequent binding of STAT1 to NLRP3 promoter region. These results suggest that low-shear stress plays a pro-atherosclerotic role by promoting endothelial cell pyroptosis through the IKKε/STAT1/NLRP3 pathway, which provides new insights into the formation of atherosclerosis.