ADAR1 and ADAR2 Expression in the Thoracic Aortic Wall Correlates with Aneurysm Severity and Dissection Risk: Insights into A-to-I RNA Editing Dysregulation in Marfan Syndrome-Derived vSMCs

Abstract

Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by ADAR1 and ADAR2, is an epitranscriptomic mechanism with emerging roles in cardiovascular disease. We investigated ADAR expression, clinical correlates, A-to-I RNA editing signatures, transcriptome and miRNA targetome in thoracic aortic aneurysm (TAA), focusing on Marfan syndrome (MFS). Immunohistochemical analysis of 58 TAA specimens (18 MFS-associated TAA, 19 tricuspid aortic valve-associated TAA (TAV), 21 bicuspid aortic valve-associated TAA (BAV)) showed the highest ADAR1 and ADAR2 in MFS. ADAR2 in vascular smooth muscle cells (vSMCs) correlated positively with aortic diameter across subtypes; ADAR1 inversely correlated with sinotubular junction dimension in MFS. Transcriptomic profiling of MFS-derived vSMC cultures identified 30 differentially expressed genes enriched in immune activation, impaired RTK signaling, and vSMC reprogramming. RNA editing analysis revealed 77 differentially edited sites across 65 genes, predominantly hypoedited in MFS, including four protein-coding recoding events at PPIL3, SLC12A6, CTSB, and VHL. miRNA seed-match analysis of 47 significant 3′UTR sites predicted 458 editing-dependent interactions across 36 genes. Only 14/36 genes showed concordant mRNA changes, suggesting that editing-dependent miRNA retargeting acts primarily at the translational level. These findings establish ADAR enzymes as candidates tissue biomarkers of TAA severity and ADAR1 as the principal driver of epitranscriptomic dysregulation in MFS aortopathy.