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<p>Although genetic risk in coronary artery disease (CAD) is linked to changes in gene expression, recent discoveries have revealed a major role for A-to-I RNA editing in CAD. ADAR1 edits immunogenic double-stranded RNA (dsRNA), preventing activation of the dsRNA sensor MDA5 (<i>IFIH1</i>) and downstream interferon-stimulated gene signaling. Using human plaque analysis and human coronary artery smooth muscle cells (SMCs), here, we show that SMCs uniquely require RNA editing and that MDA5 activation regulates SMC phenotype. In a conditional SMC-specific <i>Adar</i> deletion mouse model on an atherosclerosis-prone background, combined with <i>Ifih1</i> deletion and single-cell RNA sequencing, we demonstrate that ADAR1 preserves vascular integrity and limits atherosclerosis and calcification by suppressing MDA5 activation. Analysis of the Athero-Express carotid endarterectomy cohort further shows that interferon-stimulated gene expression correlates with SMC modulation, plaque instability and calcification. These findings reveal a fundamental mechanism of CAD, where cell type and context-specific RNA editing modulates genetic risk and vascular disease progression.</p>

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Smooth muscle expression of RNA editing enzyme ADAR1 controls activation of the RNA sensor MDA5 in atherosclerosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月16日

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  • Chad S. Weldy,
  • Qin Li,
  • João P. Monteiro,
  • Tim S. Peters,
  • Hongchao Guo,
  • Drew Galls,
  • Wenduo Gu,
  • Paul P. Cheng,
  • Markus Ramste,
  • Daniel Li,
  • Brian T. Palmisano,
  • Disha Sharma,
  • Matthew D. Worssam,
  • Quanyi Zhao,
  • Amruta Bhate,
  • Ramendra K. Kundu,
  • Trieu Nguyen,
  • Michal Mokry,
  • Clint L. Miller,
  • Sander W. van der Laan,
  • Jin Billy Li,
  • Thomas Quertermous

摘要

Although genetic risk in coronary artery disease (CAD) is linked to changes in gene expression, recent discoveries have revealed a major role for A-to-I RNA editing in CAD. ADAR1 edits immunogenic double-stranded RNA (dsRNA), preventing activation of the dsRNA sensor MDA5 (IFIH1) and downstream interferon-stimulated gene signaling. Using human plaque analysis and human coronary artery smooth muscle cells (SMCs), here, we show that SMCs uniquely require RNA editing and that MDA5 activation regulates SMC phenotype. In a conditional SMC-specific Adar deletion mouse model on an atherosclerosis-prone background, combined with Ifih1 deletion and single-cell RNA sequencing, we demonstrate that ADAR1 preserves vascular integrity and limits atherosclerosis and calcification by suppressing MDA5 activation. Analysis of the Athero-Express carotid endarterectomy cohort further shows that interferon-stimulated gene expression correlates with SMC modulation, plaque instability and calcification. These findings reveal a fundamental mechanism of CAD, where cell type and context-specific RNA editing modulates genetic risk and vascular disease progression.