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

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.