http://purl.uniprot.org/citations/32061134 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
http://purl.uniprot.org/citations/32061134 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.org/dc/terms/identifier | "doi:10.1093/cvr/cvaa036"xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/author | "Mura M."xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/author | "Ronchi C."xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/author | "Bernardi J."xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/author | "Rocchetti M."xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/author | "Schwartz P.J."xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/author | "Crotti L."xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/author | "Gnecchi M."xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/author | "Zaza A."xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/author | "Brink P."xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/author | "Stefanello M."xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/author | "Badone B."xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/date | "2021"xsd:gYear |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/name | "Cardiovasc Res"xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/pages | "472-483"xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/title | "NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis."xsd:string |
http://purl.uniprot.org/citations/32061134 | http://purl.uniprot.org/core/volume | "117"xsd:string |
http://purl.uniprot.org/citations/32061134 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/32061134 |
http://purl.uniprot.org/citations/32061134 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/32061134 |
http://purl.uniprot.org/uniprot/#_A0PJJ7-mappedCitation-32061134 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/32061134 |
http://purl.uniprot.org/uniprot/#_B4DG68-mappedCitation-32061134 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/32061134 |
http://purl.uniprot.org/uniprot/#_B3VK56-mappedCitation-32061134 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/32061134 |
http://purl.uniprot.org/uniprot/#_P29475-mappedCitation-32061134 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/32061134 |