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

Area of Science:

• Cardiovascular Biology
• Epigenetics
• Vascular Biology

Background:

• Vascular calcification (VC) is driven by osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs).
• Runt-related transcription factor 2 (RUNX2) is a key osteogenic transcription factor in VSMCs.
• Ten-eleven translocation 2 (TET2), a DNA demethylation enzyme, is vital for maintaining the VSMC phenotype.

Purpose of the Study:

• To investigate the role of TET2 in the progression of vascular calcification.
• To elucidate the underlying molecular mechanisms by which TET2 influences VC.

Main Methods:

• Analysis of TET2 expression in calcified human and mouse arteries and VSMCs.
• In vitro gain- and loss-of-function experiments to assess TET2's effect on VC.
• In vivo studies using vitamin D3- and adenine diet-induced chronic kidney disease (CKD) mouse models with TET2 knockdown.
• Chromatin immunoprecipitation and co-immunoprecipitation assays to determine molecular interactions.

Main Results:

• TET2 expression was significantly downregulated in calcified arteries and VSMCs.
• TET2 loss-of-function exacerbated VC in vivo in mouse models.
• TET2 directly bound to and suppressed the P2 promoter of the RUNX2 gene.
• TET2 formed a complex with HDAC1/2 to deacetylate H3K27ac on the RUNX2 P2 promoter, inhibiting transcription.
• SNIP1 was essential for TET2-HDAC1/2 interaction and VC inhibition; SNIP1 knockdown accelerated VC.

Conclusions:

• TET2 plays a critical inhibitory role in vascular calcification.
• TET2 functions by epigenetically repressing RUNX2 transcription via interaction with HDAC1/2 and SNIP1.
• TET2 represents a potential therapeutic target for treating vascular calcification.