TET1s deficiency exacerbates oscillatory shear flow-induced atherosclerosis

Background: TET1 has been implicated in regulating inflammation and cardiovascular disease, but a newly discovered short isoform of TET1 (termed TET1s) exhibits higher expression in adult tissues than full-length TET1. However, the precise role of TET1 in cardiovascular disease remains undefined. Methods and Results: Based on TET1 knockout mice (with deletion of both TET1 and TET1s ) and TET1 mice (with deletion of only TET1), we found that TET1s deletion in TET1 mice resulted in more serious atherosclerotic lesions in the whole aorta than TET1cs/cs in the ApoE background mice fed a high-fat diet. Atherosclerotic lesions with Oil red staining were dramatically localized in the aortic arch, abdominal aorta and ligated LCA, where they were exposed to OSS. Furthermore, the OSS-induced depression of TET1s in vitro and in vivo increased inflammatory cell and red blood cell infiltration into the subendothelial layer by impairing the vascular intimal barrier. TET1s upregulation enhanced vascular endothelial barrier function by increasing gap protein connexin 40 (CX40) expression as measured by RNA-seq and was confirmed by CX40 knockdown. TET1s interaction with Sin3a increased the global and CX40 promoter histone H3K27 acetylation levels, but not DNA methylation, to induce CX40 expression. Conclusions: These data demonstrate the unexpected discovery that laminar shear stress induces TET1s expression to protect the vascular endothelial barrier by increasing CX40 expression in ECs and that TET1s overexpression may be the core step for OSS-induced atherosclerosis therapy.