Endothelial <scp>KDM5B</scp> Regulated by Piezo1 Contributes to Disturbed Flow Induced Atherosclerotic Plaque Formation

Epigenetic modifications play an important role in disturbed flow (d-flow) induced atherosclerotic plaque formation. By analysing a scRNA-seq dataset of the left carotid artery (LCA) under d-flow conditions, we found that Jarid1b (KDM5B) was upregulated primarily in a subcluster of endothelial cells in response to d-flow stimulation. We therefore investigated the mechanism of KDM5B expression and the role of KDM5B in endothelial cell. Intriguingly, activation of Piezo1, a major endothelial mechanosensor, was found to promote KDM5B expression, which was reversed by Piezo1 inhibition in HUVECs. Downstream of Piezo1, ETS1 expression and c-JUN phosphorylation were enhanced by d-flow or Piezo1 activation, leading to an increase in KDM5B expression. Furthermore, knockdown of either KDM5B or Piezo1 was found to prevent d-flow induced H3K4me3 demethylation, which was supported by the pharmacological inhibition of Piezo1 in HUVECs. RNA sequencing on shKdm5b HUVECs implied that KDM5B is associated with endothelial inflammation and atherosclerosis. Using partial carotid ligation surgery on Kdm5b^f/f Cdh5^cre mice with mAAV-PCSK9^D377Y infected, we showed that endothelial KDM5B deficiency reduced atherosclerotic lesions in hypercholesterolemic mice. Our findings indicate that endothelial KDM5B expression induced by d-flow via the Piezo1 pathway promotes atherosclerotic plaque formation, providing targets for the prevention or therapeutic intervention of atherosclerosis.