Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering Chongqing University, Chongqing, China.
Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen, China.
Int J Biol Sci. 2022 Feb 28;18(5):2163-2180. doi: 10.7150/ijbs.69281. eCollection 2022.
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. Based on knockout mice (with deletion of both TET1 and TET1s ) and mice (with deletion of only TET1), we found that TET1s deletion in mice resulted in more serious atherosclerotic lesions in the whole aorta than TET1cs/cs in the 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 and 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. 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.
TET1 被认为参与调节炎症和心血管疾病，但最近发现的 TET1 的一种短亚型（称为 TET1s）在成人组织中的表达高于全长 TET1。然而，TET1 在心血管疾病中的确切作用仍未确定。基于敲除小鼠（同时缺失 TET1 和 TET1s）和条件敲除小鼠（仅缺失 TET1），我们发现与 背景下的 TET1cs/cs 相比，高脂饮食喂养的 背景下的 TET1s 敲除小鼠的整个主动脉中的动脉粥样硬化病变更严重。用 Oil red 染色的动脉粥样硬化病变明显定位于主动脉弓、腹主动脉和结扎的 LCA，这些部位暴露于 OSS。此外，OSS 诱导的 TET1s 下调和血管内皮屏障功能障碍导致炎症细胞和红细胞渗入血管内膜下，增加了 TET1s 的表达。TET1s 的上调通过增加间隙蛋白连接蛋白 40（CX40）的表达增强了血管内皮屏障功能，这可以通过 RNA-seq 测量并通过 CX40 敲低来证实。TET1s 与 Sin3a 的相互作用增加了 CX40 启动子的组蛋白 H3K27 乙酰化水平，但不增加 DNA 甲基化，从而诱导 CX40 的表达。这些数据表明，出乎意料的发现是层流剪切力通过增加内皮细胞中 CX40 的表达来诱导 TET1s 表达，从而保护血管内皮屏障，而 TET1s 的过表达可能是 OSS 诱导的动脉粥样硬化治疗的核心步骤。
