ArticleNature cardiovascular research2025
Smooth muscle expression of RNA editing enzyme ADAR1 controls activation of the RNA sensor MDA5 in atherosclerosis.
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Article in Nature cardiovascular research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Depletion of the RNA-Editing Enzyme ADAR1 Invigorates the Antitumor Immunity of NK Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Adenosine-to-Inosine (A-to-I) RNA Editing by ADAR1 to Control RNA Sensing in Cardiovascular Disease.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- RNA editing in cardiovascular health and disease.Communications biology · 2026Review
- A Comprehensive Review of Epigenetic Regulation of Vascular Smooth Muscle Cells During Development and Disease.Biomolecules · 2026Review
- VSMCs and the immune microenvironment: a multidimensional regulatory network driving vascular injury and repair.Frontiers in immunology · 2026Review
- Article
- A cell and transcriptome atlas of human arterial vasculature.Cell genomics · 2025Article
- RNA modifications in health and disease: from mechanistic insights to therapeutic applications.Precision clinical medicine · 2025Review
Corrections and comments
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Authors and funding
22 authors.
Chad S WeldyDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA. weldyc@stanford.edu.ORCID http://orcid.org/0000-0003-4652-6422
Qin LiDepartment of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
João P MonteiroDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.ORCID http://orcid.org/0000-0001-6481-6875
Tim S PetersCentral Diagnostic Laboratory, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands.ORCID http://orcid.org/0009-0006-4077-8089
Hongchao GuoNora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, USA.
Drew GallsDepartment of Genetics, Stanford University, Stanford, CA, USA.ORCID http://orcid.org/0000-0003-1136-0418
Wenduo GuDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.ORCID http://orcid.org/0000-0002-3859-3150
Paul P ChengDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.ORCID http://orcid.org/0000-0003-3429-2702
Markus RamsteDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Daniel LiDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.ORCID http://orcid.org/0000-0003-1015-6298
Brian T PalmisanoDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.ORCID http://orcid.org/0000-0002-2140-1060
Disha SharmaDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.ORCID http://orcid.org/0000-0001-9486-2709
Matthew D WorssamDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.ORCID http://orcid.org/0000-0003-4391-5377
Quanyi ZhaoDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Amruta BhateDepartment of Genetics, Stanford University, Stanford, CA, USA.
Ramendra K KunduDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Trieu NguyenDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Michal MokryCentral Diagnostic Laboratory, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands.ORCID http://orcid.org/0000-0002-5298-4852
Clint L MillerDepartment of Genome Sciences, University of Virginia, Charlottesville, VA, USA.ORCID http://orcid.org/0000-0003-4276-3607
Sander W van der LaanCentral Diagnostic Laboratory, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands.ORCID http://orcid.org/0000-0001-6888-1404
Jin Billy Li *Stanford Cardiovascular Institute, Stanford, CA, USA.ORCID http://orcid.org/0000-0003-0713-1399
Thomas Quertermous *Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA. tomq1@stanford.edu.ORCID http://orcid.org/0000-0002-7645-9067
Funding
Stanford Center for Connecting DNA Variants to Function and PhenotypeUM1HG011972 · NHGRI · STANFORD UNIVERSITY · PI JESSE M ENGREITZ, THOMAS QUERTERMOUS · 2021 to 2026
$10.5MScientific Core: Perturb-seq library generation, sequencing, and data analysisP01HL180323 · NHLBI · STANFORD UNIVERSITY · PI THOMAS QUERTERMOUS · 2025 to 2026
$7.1MCausal variant association mechanisms in TCF21 binding coronary disease lociR01HL134817 · NHLBI · STANFORD UNIVERSITY · PI THOMAS QUERTERMOUS · 2017 to 2026
$6.2MThe SMAD3 signaling network in coronary artery disease riskR01HL139478 · NHLBI · STANFORD UNIVERSITY · PI THOMAS QUERTERMOUS · 2018 to 2026
$3.7MRegulatory and Mechanistic Understanding of ADAR-Mediated RNA EditingR35GM144100 · NIGMS · STANFORD UNIVERSITY · PI Jin Billy Li · 2022 to 2026
$3.2MProfiling and Dissecting the Dynamic Regulation of RNA EditingR01GM102484 · NIGMS · STANFORD UNIVERSITY · PI LI, JIN BILLY · 2013 to 2021
$3.1MMolecular Drivers of Atherosclerosis in DiabetesU01DK142283 · NIDDK · UNIVERSITY OF VIRGINIA · PI Mete Civelek, Clint L Miller · 2024 to 2026
$2.9MPDGFD regulates a transcriptional network to modulate smooth muscle cell transition and coronary artery disease riskR01HL156846 · NHLBI · STANFORD UNIVERSITY · PI QUERTERMOUS, THOMAS · 2021 to 2024
$2.7MIdentifying tobacco-genetic interactions through study of the aryl hydrocarbon receptor pathway.R01HL151535 · NHLBI · STANFORD UNIVERSITY · PI QUERTERMOUS, THOMAS · 2021 to 2024
$2.7MSystematic characterization of trans regulation of A-to-I RNA editing in neuronsR01MH115080 · NIMH · STANFORD UNIVERSITY · PI LI, JIN BILLY · 2017 to 2021
$2.3MLncRNA Transcriptional Mechanisms of Coronary Artery Disease RiskR01HL145708 · NHLBI · STANFORD UNIVERSITY · PI QUERTERMOUS, THOMAS · 2019 to 2022
$1.6MAdventitial Fibroblast Phenotypic Modulation in AtherosclerosisR01HL179083 · NHLBI · STANFORD UNIVERSITY · PI Paul Po Sheng cheng · 2025 to 2026
$1.4MAmerican Heart Association (American Heart Association, Inc.) 20CDA35310303American Heart Association (American Heart Association, Inc.) 23CDA1042900American Heart Association (American Heart Association, Inc.) 23POST1018991American Heart Association (American Heart Association, Inc.) 24CDA1272805American Heart Association (American Heart Association, Inc.) 24POST1187860American Heart Association (American Heart Association, Inc.) 24SCEFIA1248386NHGRI NIH HHS UM1 HG011972NHLBI NIH HHS F32 HL160067NHLBI NIH HHS F32 HL165854NHLBI NIH HHS K08 HL153798NHLBI NIH HHS K08 HL167699NHLBI NIH HHS K08 HL177251NHLBI NIH HHS L30 HL159413NHLBI NIH HHS P01 HL180323NHLBI NIH HHS R00 HL150319NHLBI NIH HHS R01 HL134817NHLBI NIH HHS R01 HL139478NHLBI NIH HHS R01 HL145708NHLBI NIH HHS R01 HL151535NHLBI NIH HHS R01 HL156846NHLBI NIH HHS R01 HL179083NIDDK NIH HHS U01 DK142283NIGMS NIH HHS R01 GM102484NIGMS NIH HHS R35 GM144100NIMH NIH HHS R01 MH115080U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) F32HL160067U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) K08HL153798U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) K08HL167699U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) K08HL177251U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) L30HL159413U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R00HL150319U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01HL134817U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01HL139478U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01HL145708U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01HL151535U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01HL156846U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01HL179083U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) U01DK142283-01U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) R01GM102484U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) R35GM144100U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) R01MH115080
Abstract
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.
Indexed as
Adenosine DeaminaseAtherosclerosisCoronary VesselsInterferon-Induced Helicase, IFIH1Muscle, Smooth, VascularMyocytes, Smooth MuscleRNA-Binding ProteinsRNA EditingVascular CalcificationAnimalsCells, CulturedDisease Models, AnimalFemaleHumansMaleMiceADAR1 protein, mouseADAR protein, humanAdenosine DeaminaseIFIH1 protein, humanIfih1 protein, mouseInterferon-Induced Helicase, IFIH1RNA-Binding Proteins
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