NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis
| العنوان: | NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis |
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| المؤلفون: | Joyce Bernardi, Carlotta Ronchi, Manuela Mura, Manuela Stefanello, Peter J. Schwartz, Antonio Zaza, Massimiliano Gnecchi, Paul A. Brink, Lia Crotti, Marcella Rocchetti, Beatrice Badone |
| المساهمون: | RS: Carim - H04 Arrhythmogenesis and cardiogenetics, Bedrijfsbureau CD, Ronchi, C, Bernardi, J, Mura, M, Stefanello, M, Badone, B, Rocchetti, M, Crotti, L, Brink, P, Schwartz, P, Gnecchi, M, Zaza, A |
| المصدر: | Cardiovascular Research, 117(2), 472-483. Oxford University Press Cardiovasc Res |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | medicine.medical_specialty, Physiology, NOS1, Long QT syndrome, Physical Distancing, Stimulation, hiPSC-derived cardiomyocytes, Nitric Oxide Synthase Type I, NOS1 defect, Arrhythmias, QT interval, NOS1AP polymorphism, NOS1AP, BIO/09 - FISIOLOGIA, Physiology (medical), Internal medicine, medicine, Repolarization, Humans, hiPSC-derived cardiomyocyte, KvLQT1, LQT1, Adaptor Proteins, Signal Transducing, biology, business.industry, Arrhythmias, Cardiac, Original Articles, medicine.disease, Romano–Ward syndrome, Long QT Syndrome, Endocrinology, biology.protein, Cardiology and Cardiovascular Medicine, business, Arrhythmia |
| الوصف: | Aims NOS1AP 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 results In 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. Conclusion The 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. |
| اللغة: | English |
| تدمد: | 0008-6363 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b38211df5f5e393fc7e1be257fa9c347 https://cris.maastrichtuniversity.nl/en/publications/0489c8c3-755c-480b-a0cf-95d562248592 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....b38211df5f5e393fc7e1be257fa9c347 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00086363 |
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