ArticleProceedings of the National Academy of Sciences of the United States of America2014
Pitx2-microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed, 115 citations in OpenAlex.
- The cardiac conduction system: development, function and therapeutic targets.Nature reviews. Cardiology · 2026Review
- Cardiac conduction system malformations in heterotaxy result from dysregulated Pitx2 expression.JCI insight · 2026Article
- Application of Prenatal Whole Exome Sequencing for Congenital Heart Anomalies.International journal of molecular sciences · 2026Review
- Single-Nucleotide Polymorphisms,International journal of molecular sciences · 2025Review
- The Hidden Regulators: MicroRNAs in Pediatric Heart Development and Disease.Journal of clinical medicine · 2025Review
- The Pleiotropic Role of the MicroRNA-17-92 Cluster in Cardiovascular Diseases and Cancer.Reviews in cardiovascular medicine · 2025Review
- The Neglected Internodal Tract-A Cardiac Conduction System Structure Homologous to the Development and Regulation of the Sinoatrial Node.Reviews in cardiovascular medicine · 2025Review
- Circulating extra-cellular RNAs and atrial fibrillation: data from the TRACE-CORE cohort.Frontiers in cardiovascular medicine · 2025Article
- Segregation of morphogenetic regulatory function of Shox2 from its cell fate guardian role in sinoatrial node development.Communications biology · 2024Article
- Atrial fibrillation: pathophysiology, genetic and epigenetic mechanisms.The Lancet regional health. Europe · 2024Review
- Development of the Cardiac Conduction System.Advances in experimental medicine and biology · 2024Article
- The miR-17-92 cluster in cardiac health and disease.Birth defects research · 2024Review
- MicroRNAs: Midfielders of Cardiac Health, Disease and Treatment.International journal of molecular sciences · 2023Review
- Gene modules and genes associated with postoperative atrial fibrillation: weighted gene co-expression network analysis and circRNA-miRNA-mRNA regulatory network analysis.Journal of thoracic disease · 2023Article
- Circulatory miR-411-5p as a Novel Prognostic Biomarker for Major Adverse Cardiovascular Events in Patients with Atrial Fibrillation.International journal of molecular sciences · 2023Article
- Hippo-Yap Signaling Maintains Sinoatrial Node Homeostasis.Circulation · 2022Article
- Atrial AMP-activated protein kinase is critical for prevention of dysregulation of electrical excitability and atrial fibrillation.JCI insight · 2022Article
- MicroRNAs in cardiovascular diseases.Medical review (2021) · 2022Review
- Post-Transcriptional Regulation of Molecular Determinants during Cardiogenesis.International journal of molecular sciences · 2022Review
- Patient-Specific TBX5-G125R Variant Induces Profound Transcriptional Deregulation and Atrial Dysfunction.Circulation · 2022Article
12 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
The molecular mechanisms underlying atrial fibrillation, the most common sustained cardiac arrhythmia, remain poorly understood. Genome-wide association studies uncovered a major atrial fibrillation susceptibility locus on human chromosome 4q25 in close proximity to the paired-like homeodomain transcription factor 2 (Pitx2) homeobox gene. Pitx2, a target of the left-sided Nodal signaling pathway that initiates early in development, represses the sinoatrial node program and pacemaker activity on the left side. To address the mechanisms underlying this repressive activity, we hypothesized that Pitx2 regulates microRNAs (miRs) to repress the sinoatrial node genetic program. MiRs are small noncoding RNAs that regulate gene expression posttranscriptionally. Using an integrated genomic approach, we discovered that Pitx2 positively regulates miR-17-92 and miR-106b-25. Intracardiac electrical stimulation revealed that both miR-17-92 and miR-106b-25 deficient mice exhibit pacing-induced atrial fibrillation. Furthermore electrocardiogram telemetry revealed that mice with miR-17-92 cardiac-specific inactivation develop prolonged PR intervals whereas mice with miR-17-92 cardiac-specific inactivation and miR-106b-25 heterozygosity develop sinoatrial node dysfunction. Both arrhythmias are risk factors for atrial fibrillation in humans. Importantly, miR-17-92 and miR-106b-25 directly repress genes, such as Shox2 and Tbx3, that are required for sinoatrial node development. Together, to our knowledge, these findings provide the first genetic evidence for an miR loss-of-function that increases atrial fibrillation susceptibility.
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