ArticleCardiovascular research2021
NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis.
Article in Cardiovascular research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
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Who cites it
20 citing papers in PubMed, 1 synthesis or guideline pooled it, 34 citations in OpenAlex.
- Genomic data-driven framework for drug target discovery in atrial fibrillation.Journal of translational medicine · 2025Pooled it
- Machine learning-guided risk stratification for long QT syndrome genetic variants with hiPSC-derived cardiomyocytes.Cardiovascular research · 2026Article
- The Utility of Genome-Wide Association Studies in Inherited Arrhythmias and Cardiomyopathies.Genes · 2025Review
- A Meta-Narrative Review of Channelopathies and Cannabis: Mechanistic, Epidemiologic, and Forensic Insights into Arrhythmia and Sudden Cardiac Death.International journal of molecular sciences · 2025Review
- Nitric oxide synthase 1 inhibits the progression of esophageal cancer through interacting with nitric oxide synthase 1 adaptor protein.World journal of gastrointestinal oncology · 2025Article
- Induced Pluripotent Stem Cells in Congenital Long QT Syndrome: Research Progress and Clinical Applications.Reviews in cardiovascular medicine · 2025Review
- Stem cell models of inherited arrhythmias.Nature cardiovascular research · 2024Review
- Article
- Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- The Advantages, Challenges, and Future of Human-Induced Pluripotent Stem Cell Lines in Type 2 Long QT Syndrome.Journal of cardiovascular translational research · 2023Review
- Inducible over-expression of cardiac Nos1ap causes short QT syndrome in transgenic mice.FEBS open bio · 2023Article
- A NOS1AP gene variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin.The pharmacogenomics journal · 2022Article
- Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population.Biomedicines · 2022Review
- Characterization of the PLN p.Arg14del Mutation in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.International journal of molecular sciences · 2021Article
- ESC working group on cardiac cellular electrophysiology position paper: relevance, opportunities, and limitations of experimental models for cardiac electrophysiology research.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2021Review
- Mechanoelectric coupling and arrhythmogenesis in cardiomyocytes contracting under mechanical afterload in a 3D viscoelastic hydrogel.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Human induced pluripotent stem cell-derived atrial cardiomyocytes carrying an SCN5A mutation identify nitric oxide signaling as a mediator of atrial fibrillation.Stem cell reports · 2021Article
- 'Social distancing' of the neuronal nitric oxide synthase from its adaptor protein causes arrhythmogenic trigger-substrate interactions in long QT syndrome.Cardiovascular research · 2021Article
- Neurological Disorders and Risk of Arrhythmia.International journal of molecular sciences · 2020Review
- Mechanisms of Cav3-associated arrhythmia: Protein or microdomain dysfunction?International journal of cardiology · 2020Article
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11 authors at 6 institutions in 3 countries.
Funding
Abstract
aimsNOS1AP single-nucleotide polymorphisms (SNPs) correlate with QT prolongation and cardiac sudden death in patients affected by long QT syndrome type 1 (LQT1). NOS1AP targets NOS1 to intracellular effectors. We hypothesize that NOS1AP SNPs cause NOS1 dysfunction and this may converge with prolonged action-potential duration (APD) to facilitate arrhythmias. Here we test (i) the effects of NOS1 inhibition and their interaction with prolonged APD in a guinea pig cardiomyocyte (GP-CMs) LQT1 model; (ii) whether pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from LQT1 patients differing for NOS1AP variants and mutation penetrance display a phenotype compatible with NOS1 deficiency. METHODS AND
resultsIn GP-CMs, NOS1 was inhibited by S-Methyl-L-thiocitrulline acetate (SMTC) or Vinyl-L-NIO hydrochloride (L-VNIO); LQT1 was mimicked by IKs blockade (JNJ303) and β-adrenergic stimulation (isoproterenol). hiPSC-CMs were obtained from symptomatic (S) and asymptomatic (AS) KCNQ1-A341V carriers, harbouring the minor and major alleles of NOS1AP SNPs (rs16847548 and rs4657139), respectively. In GP-CMs, NOS1 inhibition prolonged APD, enhanced ICaL and INaL, slowed Ca2+ decay, and induced delayed afterdepolarizations. Under action-potential clamp, switching to shorter APD suppressed 'transient inward current' events induced by NOS1 inhibition and reduced cytosolic Ca2+. In S (vs. AS) hiPSC-CMs, APD was longer and ICaL larger; NOS1AP and NOS1 expression and co-localization were decreased.
conclusionThe minor NOS1AP alleles are associated with NOS1 loss of function. The latter likely contributes to APD prolongation in LQT1 and converges with it to perturb Ca2+ handling. This establishes a mechanistic link between NOS1AP SNPs and aggravation of the arrhythmia phenotype in prolonged repolarization syndromes.
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