The Short Isoform TET1s Retards Oscillatory Shear Flow-Induced Atherosclerosis Through CX40-Dependent Endothelial Cell Barrier Enhancement

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: To assess the function of TET1s in atherosclerosis development, ApoE-/-TET1-/- mice and ApoE-/-TET1cs/cs mice were generated. Atherosclerotic plaques were evaluated by Oil red staining and endothelial permeability was accessed by Evans blue staining. Oscillatory shear stress (OSS) model generated by carotid artery ligation. Overexpressing TET1s in primary HUVECs was used to access the function of TET1s in vitro. Findings: 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. Atherosclerotic lesions 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 impaired the vascular intimal barrier. TET1s upregulation enhanced vascular endothelial barrier function by increasing CX40 expression through increases histone acetylation levels in the CX40 promoter via its interaction with Sin3a. Interpretation: These data demonstrate TET1s expression to protect OSS-induced atherosclerosis through enhancing vascular endothelial barrier by increasing CX40 expression in ECs Funding: The work is supported by the Natural Science Foundation of China (31971242, 12032007), Chongqing Science and Technology Bureau (cstc2019jcyj-zdxmX0028) and Fundamental Research Funds for Central Universities (2019CDYGZD008, 2019CDYGYB016, 2021CDJCGJ007). Declaration of Interest: All authors declare no conflict of interest Ethical Approval: All animal procedures and patients sample study were reviewed and approved by the Animal Care and Ethic Committee of Chongqing University.