N6-methyladenosine epitranscriptomic remodeling drives infantile aortic coarctation via FTO-mediated repression of PTEN and GRK5
TL;DR
It is found that global m6A levels are significantly elevated in CoA tissues, with widespread hypermethylation events enriched in focal adhesion and extracellular matrix remodeling pathways, providing novel epigenetic targets for therapeutic intervention.
Abstract
Introduction Aortic coarctation (CoA) is a prevalent congenital heart defect defined by focal aortic narrowing and progressive fibrosis, associated with substantial long-term cardiovascular morbidity. Although surgical repair improves early survival, the molecular and epigenetic mechanisms governing CoA pathogenesis remain poorly understood. N6-methyladenosine (m6A), the most abundant internal mRNA modification, regulates post-transcriptional gene expression during cardiovascular development and disease. In this study, we investigated whether dysregulated m6A epitranscriptome contributes to infantile CoA. Methods Global m6A abundance was measured in stenotic aortic tissues and paired normal aortic segments from infants with CoA using dot blot and colorimetric assays. Transcriptome-wide m6A landscapes were profiled by methylated RNA immunoprecipitation sequencing (MeRIP-seq), and mRNA expression patterns were determined by RNA sequencing (RNA-seq). Quantitative real-time PCR (qRT-PCR) was used to validate key genes and m6A regulatory factors. To establish causal regulatory relationships, we further performed FTO loss-of-function knockdown experiments in human aortic smooth muscle cells (HASMCs). Results We found that global m6A levels are significantly elevated in CoA tissues, with widespread hypermethylation events enriched in focal adhesion and extracellular matrix remodeling pathways. Integrated multi-omics analysis identified FTO (alpha-ketoglutarate dependent dioxygenase) downregulation as the primary driver of m6A hypermethylation in CoA. Mechanistically, reduced FTO expression increases m6A methylation of phosphatase and tensin homolog (PTEN) and G protein-coupled receptor kinase 5 (GRK5), resulting in their transcriptional repression in stenotic aortic tissue. In HASMCs, silencing FTO directly elevated m6A modification and suppressed PTEN and GRK5 expression. Functionally, diminished PTEN expression promotes aortic smooth muscle fibrosis and luminal narrowing. Conclusion Our findings uncover a previously unrecognized FTO/m6A/PTEN epitranscriptomic axis that governs infantile CoA pathogenesis, providing novel epigenetic targets for therapeutic intervention.