TET2 suppresses vascular calcification by forming inhibitory complex with HDAC1/2 and SNIP1 independent of demethylation

去甲基化 抑制性突触后电位 钙化 化学 生物 药理学 生物化学 细胞生物学 医学 神经科学 DNA甲基化 内科学 基因 基因表达
作者
Dajiang He,Jianshuai Ma,Zhen Zhou,Yanli Qi,Yaxin Lian,Feng Wang,Huiyong Yin,Huanji Zhang,Tingting Zhang,Hui Huang
出处
期刊:Journal of Clinical Investigation [American Society for Clinical Investigation]
标识
DOI:10.1172/jci186673
摘要

Osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) has been recognized as the principal mechanism underlying vascular calcification (VC). Runt-related transcription factor 2 (RUNX2) in VSMCs plays a pivotal role because it constitutes an essential osteogenic transcription factor for bone formation. As a key DNA demethylation enzyme, ten-eleven translocation 2 (TET2) is crucial in maintaining the VSMC phenotype. However, whether TET2 involves in VC progression remains elusive. Here we identified a substantial downregulation of TET2 in calcified human and mouse arteries, as well as human primary VSMCs. In vitro gain- and loss-of function experiments demonstrated TET2 regulated VC. Subsequently, in vivo knockdown of TET2 significantly exacerbated VC in both vitamin D3 and adenine-diet-induced chronic kidney disease (CKD) mice models. Mechanistically, TET2 binds to and suppresses the activity of the P2 promoter within the RUNX2 gene, whereas an enzymatic loss-of-function mutation of TET2 has a comparable effect. Furthermore, TET2 forms a complex with histone deacetylases 1/2 (HDAC1/2 ) to deacetylate H3K27ac on the P2 promoter, thereby inhibiting its transcription. Moreover, SNIP1 is indispensable for TET2 to interact with HDAC1/2 to exert inhibitory effect on VC, and knockdown of SNIP1 accelerated VC in mice. Collectively, our findings imply that TET2 might serve as a potential therapeutic target for VC.

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