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September 17, 2026Cardiovascular Research

Targeting circILRUN or NAT10 attenuates aortic valve calcification in mice by disrupting the sEV-circILRUN-NAT10-CD36 axis.

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Why the study?

Calcific aortic valve disease lacks effective pharmacotherapies and the mechanism by which oscillatory shear stress-induced extracellular vesicles promote aortic valve calcification is unknown.

Does genetic ablation of circILRUN or pharmacological inhibition of NAT10 reduce aortic valve calcification in preclinical models?

Population

Human valvular endothelial cells, human valvular interstitial cells, and two independent mouse models of aortic valve calcification

Comparison

Genetic ablation of circILRUN or pharmacological inhibition of NAT10 vs control

Design

Preclinical mechanistic study

Key result

Genetic ablation of circILRUN or pharmacological inhibition of NAT10 attenuated aortic valve calcification in mouse models by disrupting the OSS-induced sEV-circILRUN-NAT10-CD36 axis.

Authors

SCShiqi ChenXSXiaoke ShangJXJianjun Xu

Discussion

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Member takes

Overview

May identify NAT10 inhibition as a target for aortic valve calcification; hypothesis-generating in mice but leaves open human translation.

Key Points

  • To identify the mechanosensitive molecular pathway by which endothelial small extracellular vesicles transmit oscillatory shear stress signals to drive aortic valve calcification.
  • CircRNA microarray sequencing was conducted on small extracellular vesicles (sEVs) derived from oscillatory shear stress-stimulated human valvular endothelial cells (hVECs).
  • Endothelial-interstitial cellular crosstalk was evaluated in human valvular interstitial cells (hVICs) exposed to sEVs, alongside testing in two independent mouse models using genetic ablation of circILRUN.
  • Molecular interactions and downstream epitranscriptomic targets were mapped using integrated ac4C acetylome and transcriptome profiling, supported by in vivo pharmacological inhibition of NAT10.
  • CircILRUN was identified as the most significantly upregulated circRNA in OSS-induced sEVs, which transferred to hVICs and promoted osteogenic reprogramming.
  • Genetic ablation of circILRUN attenuated calcium deposition and improved echocardiographic parameters in two mouse models of aortic valve calcification.
  • Mechanistically, circILRUN functioned as a scaffold recruiting USP11 to deubiquitinate and stabilize NAT10, which ac4C-modified and stabilized CD36 mRNA; pharmacologic inhibition of NAT10 successfully reversed pro-calcific signaling in vitro and in vivo.

Structured PICO

Does genetic ablation of circILRUN or pharmacological inhibition of NAT10 reduce aortic valve calcification in preclinical models?

P
Population
Human valvular endothelial cells (hVECs), human valvular interstitial cells (hVICs), and two independent mouse models of aortic valve calcification
I
Intervention
Genetic ablation of circILRUN or pharmacological inhibition of NAT10
C
Comparator
Control/vehicle (implied)
O
Outcome
Aortic valve calcification (assessed by echocardiographic parameters and calcium deposition)surrogate

This study identifies a novel mechanosensitive pathway (sEV-circILRUN-NAT10-CD36 axis) driving aortic valve calcification and highlights NAT10 as a potential therapeutic target.

Cite This Study

Chen et al. (2026) studied Calcific aortic valve disease (CAVD). Genetic ablation of circILRUN or pharmacological inhibition of NAT10 was evaluated on Aortic valve calcification. Genetic ablation of circILRUN or pharmacological inhibition of NAT10 attenuated aortic valve calcification in mouse models by disrupting the OSS-induced sEV-circILRUN-NAT10-CD36 axis.

synapsesocial.com/papers/6aabb7755f706d05830e6721https://doi.org/10.1093/cvr/cvag205
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Calcific aortic valve disease augments vesicular microRNA-145-5p to regulate the calcification of valvular interstitial cells via cellular crosstalk2025
  2. 2Aortic valve disease augments vesicular microRNA-145-5p to regulate the calcification of valvular interstitial cells via cellular crosstalk2022
  3. 3Calcific aortic valve disease augments vesicular microRNA-145-5p to regulate the calcification of valvular interstitial cells via cellular crosstalk2025 · 5 citations
  4. 4Endothelial Notch signaling as a target for aortic valve calcification2025
  5. 5The Role of Valve Endothelial Cells in Aortic Valve Calcification2025