Laminar shear stress inhibits inflammation by activating autophagy in human aortic endothelial cells through HMGB1 nuclear translocation

Laminar shear stress (LSS) plays a variety of biological roles, one of which is regulation of gene expression in vascular endothelial cells. Prevention and treatment of atherosclerosis by targeting the inflammatory response in vascular endothelial cells has attracted much attention in recent years. In this study, we found that LSS could specifically inhibit the increased expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), cyclooxygenase-2 (COX-2), and matrix metallopeptidase-9 (MMP-9) caused by tumor necrosis factor-α (TNF-α) stimulation in an autophagy-dependent pathway in human aortic endothelial cells (HAECs) and human umbilical vein endothelial cells (HUVECs). Whole-transcriptome sequencing analysis revealed that erythropoietin-producing hepatocyte receptor B2 (EPHB2) was a key gene in response to LSS. Moreover, co-immunoprecipitation (co-IP) assay indicated that LSS could activate autophagy flux by enhancing the EPHB2-mediated nuclear translocation of high mobility group box-1 (HMGB1), which interacts with Beclin-1 (BECN1) and finally leads to autophagy in HAECs. We also found that overexpression of EPHB2 can activate autophagy and exert the same anti-inflammatory effect as LSS. Simultaneously, we identified a novel LSS-sensitive long non-coding RNA (lncRNA), LOC10798635, and constructed an LSS-related LOC107986345/miR-128-3p/EPHB2 regulatory axis. Further research revealed the inhibition of endothelial inflammatory by LSS depends on autophagy activation resulting from the nuclear translocation of HMGB1 via the LOC107986345/miR-128-3p/EPHB2 axis. In conclusion, our study demonstrates for the first time that LSS regulates the expression of EPHB2 in HAECs, and the LOC107986345/miR-128-3p/EPHB2 axis plays a vital role in atherosclerosis development. This study included 3 samples, each with 3 replicates, where HAEC_0dy_0h was the control group.