Oscillatory shear stress mediates endothelial cell senescence by regulating endoplasmic reticulum stress through HMOX1

Oscillatory shear stress (OSS) can induce senescence in endothelial cells (ECs), driving atherosclerosis (AS), while the role of endoplasmic reticulum stress (ERS) remains unclear. OSS induced senescence in ECs by increasing SA-β-gal staining levels and upregulating p53, p21, and p16 levels, as well as the senescence-associated secretory phenotype (SASP). The SASP factors IL-1β, MIP-1α, and TNFα indicated the activation of the p53/p21 pathway. Transcriptomic analysis (GSE276195) showed that OSS activated ERS, enriched signaling pathways, and upregulated the expression levels of core ERS markers such as ATF4, IRE1α, and BIP. By using 4-PBA markedly inhibit ERS, the OSS-induced senescence. The integrated WGCNA and PPI analyses identified HMOX1 as a central hub gene, which was proven by in vivo and in vitro experiments. It displayed increased expression following OSS treatment and co-expression with ERS-genes. By inhibiting HMOX1 expression using Znpp, we found that HMOX1 suppression decreased the upregulation of ERS markers (BIP and IRE1α) and senescence markers (p53 and p21) induced by OSS; however, co-treatment with tunicamycin and HMOX1 silencing restored these upregulated levels, further demonstrating the importance of HMOX1-dependent mediation of ERS-induced senescence. This study elucidated the OSS-HMOX1-ERS axis governing senescence in ECs and suggested that HMOX1-mediated ERS plays a pivotal role in AS.