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November 9, 2026Acta Pharmacologica SinicaOpen Access

The TET2–H19 axis modulates the osteogenic differentiation of smooth muscle cells and atherosclerotic calcification

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Key result

VSMC Tet2 deficiency accelerates atherosclerotic calcification via RUNX2, whereas Tet2 overexpression attenuates it.

P=0.0021
n=11

Why the study?

Atherosclerotic calcification increases plaque vulnerability and rupture risk, but no approved medical therapies prevent it, and the effects and molecular mechanisms of TET2 deficiency and overexpression in this process were unclear.

Does TET2 expression and calpain inhibition modulate the osteogenic differentiation of vascular smooth muscle cells and prevent atherosclerotic calcification in preclinical models?

Key Points

To investigate the role and downstream mechanisms of ten-eleven translocation-2 (TET2) deficiency and overexpression in smooth muscle cell osteogenic differentiation and atherosclerotic calcification.
Evaluated TET2 expression and activity in calcified human coronary arteries, vitamin D3-induced calcified aortas, and diet-induced atherosclerotic murine aortas.
Performed single-cell transcriptomic profiling and phenotypic analyses in vascular smooth muscle cell (VSMC)-specific Tet2-deficient and Tet2-overexpressing mice.
Used siRNA knockdown, ChIP-qPCR, and the calpain inhibitor PD150606 in primary human coronary artery smooth muscle cells to trace epigenetic and osteogenic signaling.
Single-cell transcriptomic analysis showed marked expansion of the osteochondrogenic cluster in VSMC-specific Tet2-deficient mice, alongside significantly increased calcification and collagen deposition in atherosclerotic lesions.
VSMC-specific Tet2 overexpression significantly ameliorated atherosclerotic calcification.
TET2 knockdown induced H19-mediated and RUNX2-dependent osteogenic differentiation via increased H3K4me3 at the H19 promoter, whereas calpain inhibition attenuated high calcium-induced TET2 destabilization.

Structured PICO

Does TET2 expression and calpain inhibition modulate the osteogenic differentiation of vascular smooth muscle cells and prevent atherosclerotic calcification in preclinical models?

P

Population

Preclinical study utilizing 11 human coronary artery transplant specimens (7 coronary heart disease, 4 dilated cardiomyopathy controls), male VSMC-specific Tet2 knockout and overexpressing mouse models of calcification, and cultured primary human and mouse VSMCs.

I

Intervention

VSMC-specific Tet2 knockout or overexpression (induced by tamoxifen 40 mg/kg/day IP for 5 days in mice; siRNA or adenoviral AD-TET2 in cells), and calpain-specific protease inhibitor PD150606 (3 mg/kg/day IP for 5 days in vivo; 40 µM for 7 days in vitro).

C

Comparator

Vehicle control (corn oil, DMSO/saline), empty vector/scrambled control in cells, wild-type mice, and non-calcified coronary arteries from patients with dilated cardiomyopathy (non-CHD control).

O

Outcome

Vascular and atherosclerotic calcification (assessed by Alizarin Red S staining, von Kossa staining, ALP activity, and calcium content) and VSMC osteogenic differentiation (RUNX2, BMP2, MSX2, SPARC, and contractile markers ACTA2, CNN1, TAGLN) at 10 days (VitD3 model) or 20 weeks (diet-induced atherosclerosis model).surrogate

Main Result

p-value: p=0.0021

Limitations

Only male mice were used in animal experiments because the Myh11-CreERT2 bacterial artificial chromosome transgene was integrated into the Y chromosome
Small human tissue sample size (n=7 CHD and n=4 DCM controls)
Only male mice were used in the animal experiments because the Myh11-CreERT2 transgene was integrated into the Y chromosome

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Implication

Restoring TET2 expression or inhibiting calpain-mediated TET2 degradation prevents VSMC osteogenic transition and may serve as a novel therapeutic strategy against atherosclerotic calcification.

Abstract

Atherosclerotic calcification, which is characterized by the osteogenic differentiation of vascular smooth muscle cells (VSMCs), is prevalent in advanced lesions and contributes to increased plaque vulnerability and the likelihood of rupture, but no approved medical therapies are available to effectively prevent this condition. Here, we investigated the effects of ten-eleven translocation-2 (Tet2) deficiency and overexpression on atherosclerotic calcification, as well as the underlying molecular mechanisms. We found that the expression and activity of TET2 were decreased in calcified human coronary arteries, vitamin D3 overload-induced calcified aortas and diet-induced atherosclerotic aortas. The single-cell transcriptomic analysis revealed that the osteochondrogenic cluster was markedly expanded in VSMC-specific Tet2-deficient mice. Atherosclerotic lesions from VSMC-specific Tet2-deficient mice showed significantly increased calcification and deposition of collagen, whereas VSMC-specific Tet2 overexpression ameliorated atherosclerotic calcification. TET2 knockdown induced the H19-mediated and RUNX2 (runt-related transcription factor 2)-dependent osteogenic differentiation of primary human VSMCs via increased trimethylation of histone H3 lysine 4 at the H19 promoter. Treatment with a calpain inhibitor significantly inhibited calpain activity, attenuated high calcium-induced TET2 destabilization and protected against vascular calcification. Restoring TET2 expression may represent an effective strategy to protect against atherosclerotic calcification.

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Cite This Study

Zeng et al. (2026) studied Atherosclerotic calcification and coronary heart disease (n=11). VSMC-specific Tet2 deficiency, Tet2 overexpression, and calpain inhibitor PD150606 vs. Vehicle control (corn oil or DMSO/saline), wild-type mice, or non-CHD dilated cardiomyopathy human coronary arteries was evaluated on Atherosclerotic and vascular calcification, VSMC osteogenic differentiation (RUNX2 expression), and TET2/5hmC levels (p=0.0021). VSMC-specific Tet2 deficiency increased atherosclerotic calcification and osteogenic differentiation via H19/RUNX2, whereas Tet2 overexpression and calpain inhibition attenuated calcification.

synapsesocial.com/papers/6af404fa82354de27a4adb64 https://doi.org/10.1038/s41401-026-01955-x

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