Smooth muscle expression of RNA editing enzyme ADAR1 controls activation of the RNA sensor MDA5 in atherosclerosis
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.
Authors
- Clint L. Miller (ORCID: https://orcid.org/0000-0003-4276-3607)
- Hongchao Guo (ORCID: https://orcid.org/0000-0002-8884-7358)
- Trieu Nguyen (ORCID: https://orcid.org/0000-0001-5647-1301)
- Tanya Peters
- Amruta Bhate (ORCID: https://orcid.org/0000-0002-8570-2372)
- João P Monteiro (ORCID: https://orcid.org/0000-0001-6481-6875)
- Disha Sharma (ORCID: https://orcid.org/0000-0001-9486-2709)
- Matthew D. Worssam (ORCID: https://orcid.org/0000-0003-4391-5377)
- Quanyi Zhao (ORCID: https://orcid.org/0000-0001-9849-4528)
- Thomas Quertermous (ORCID: https://orcid.org/0000-0002-7645-9067)
- Sander W. van der Laan (ORCID: https://orcid.org/0000-0001-6888-1404)
- Brian T. Palmisano (ORCID: https://orcid.org/0000-0002-2140-1060)
- Drew Galls (ORCID: https://orcid.org/0000-0003-1136-0418)
- Wenduo Gu (ORCID: https://orcid.org/0000-0002-3859-3150)
- D. Li (ORCID: https://orcid.org/0000-0003-1015-6298)
- Markus Ramste (ORCID: https://orcid.org/0000-0003-4048-4591)
- Jin Billy Li (ORCID: https://orcid.org/0000-0003-0713-1399)
- Chad S. Weldy (ORCID: https://orcid.org/0000-0003-4652-6422)
- Michal Mokrý (ORCID: https://orcid.org/0000-0002-5298-4852)
- Paul P. Cheng (ORCID: https://orcid.org/0000-0003-3429-2702)
- Qin Li (ORCID: https://orcid.org/0000-0002-8948-2717)
- Ramendra K. Kundu
Institutions
- Utrecht University (NL)
- University of Utah (US)
- Cardiovascular Institute of the South (US)
- University Medical Center Utrecht (NL)
- Stanford Health Care (US)
- Stanford Medicine (US)
- University of Virginia (US)
- University of Pennsylvania (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Cardiovascular Research
- Published
- 2025-09-16
- DOI
- https://doi.org/10.1038/s44161-025-00710-5
- Citations
- 6
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 4.84