TET1 Alternative Isoform Regulates Oscillatory Shear Stress Induced Endothelial Dysfunction

Abstract

Oscillatory shear stress (OSS) is one of the major risk factors related to endothelial (EC) dysfunction, which contributes to atherosclerosis. Our previous study indicated that inhibitor of DNA binding1 (Id1) play vital role in the regulation of OSS mediated EC function related to atherosclerosis. However, the initiation mechanism during this process remains to be elucidated. Ten-eleven Translocation protein 1 alternative isoform (Tet1s) is a newly reported protein that may have function in adult tissue. Here, we investigate the role of Tet1s in regulating OSS mediated endothelial dysfunction and its underlying mechanism.     First, physical interaction between Tet1s and Id1 was found and proved by immunoprecipitation. By using carotid partial ligation mice model in vivo and OSS applied on human umbilical venous endothelial cell (HUVEC) in vitro, we found that EC proliferation rate and adhesion molecule expression were upregulated in the local area with OSS characteristics. Compared to the grater curvature (laminar shear stress), a lower Tet1s expression level in atheroprone lesser curvature (OSS) suggested Tet1s regulate the EC function under OSS. This notion is supported by the decline of Tet1s expression in cell culture model. In order to explore the Tet1s expression regulated mechanism, the potential binding sites in Tet1s promoter region for CEBPB was identified by in silico analysis. By using PKA/CEBPB inhibitor H89, we found that H89 inhibited Tet1s expression. HUVEC cell proliferation, proinflammation gene expression as well as monocytes adhesion were enhanced after knockdown of Tet1s  by specific siRNA. And overexpression of Tet1s eliminated OSS induced HUVEC proliferation and inflammation. Further studies revealed Tet1s negatively regulated the expression of Id1. Meanwhile, knockdown of Tet1s induced nucleocytoplasmic shuttling of Id1.     Our finding indicates a significant role of Tet1s in regulating OSS mediated endothelial dysfunction with respect of abnormal proliferation and inflammation though Id1-dependent pathway.