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

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Abstract

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 osteogenic transcription factor essential 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 that TET2 regulated VC. Subsequently, in vivo knockdown of TET2 significantly exacerbated VC in both vitamin D3– and adenine diet–induced chronic kidney disease (CKD) mouse models. Mechanistically, TET2 bound to and suppressed activity of the P2 promoter within the RUNX2 gene; however, an enzymatic loss-of-function mutation of TET2 did not change its binding and suppressive effects. Furthermore, TET2 formed a complex with histone deacetylases 1/2 (HDAC1/2) to deacetylate H3K27ac on the P2 promoter, thereby inhibiting its transcription. Moreover, SNIP1 was indispensable for TET2 to interact with HDAC1/2 to exert an 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.

Authors

Dayu He, Jianshuai Ma, Ziting Zhou, Yanli Qi, Yaxin Lian, Feng Wang, Huiyong Yin, Huanji Zhang, Tingting Zhang, Hui Huang