دورية أكاديمية
أعرض في EDS

The electrophysiologic effects of KCNQ1 extend beyond expression of IKs: evidence from genetic and pharmacologic block.

التفاصيل البيبلوغرافية
العنوان: The electrophysiologic effects of KCNQ1 extend beyond expression of IKs: evidence from genetic and pharmacologic block.
المؤلفون: Wada Y; Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232, USA., Wang L; Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232, USA., Hall LD; Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232, USA., Yang T; Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232, USA., Short LL; Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232, USA., Solus JF; Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232, USA., Glazer AM; Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232, USA., Roden DM; Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232, USA.; Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232, USA.
المصدر: Cardiovascular research [Cardiovasc Res] 2024 May 29; Vol. 120 (7), pp. 735-744.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Oxford Journals Country of Publication: England NLM ID: 0077427 Publication Model: Print Cited Medium: Internet ISSN: 1755-3245 (Electronic) Linking ISSN: 00086363 NLM ISO Abbreviation: Cardiovasc Res Subsets: MEDLINE
أسماء مطبوعة: Publication: 2008- : Oxford : Oxford Journals
Original Publication: London, British Medical Assn.
مواضيع طبية MeSH: KCNQ1 Potassium Channel*/genetics , KCNQ1 Potassium Channel*/metabolism , Myocytes, Cardiac*/drug effects , Myocytes, Cardiac*/metabolism , Myocytes, Cardiac*/pathology , Action Potentials*/drug effects , Induced Pluripotent Stem Cells*/metabolism , Induced Pluripotent Stem Cells*/drug effects , Moxifloxacin*/pharmacology , Phenethylamines*/pharmacology , Sulfonamides*/pharmacology , Jervell-Lange Nielsen Syndrome*/genetics , Jervell-Lange Nielsen Syndrome*/metabolism , Jervell-Lange Nielsen Syndrome*/physiopathology, Humans ; Potassium Channel Blockers/pharmacology ; Fluoroquinolones/pharmacology
مستخلص: Aims: While variants in KCNQ1 are the commonest cause of the congenital long QT syndrome, we and others find only a small IKs in cardiomyocytes from human-induced pluripotent stem cells (iPSC-CMs) or human ventricular myocytes.
Methods and Results: We studied population control iPSC-CMs and iPSC-CMs from a patient with Jervell and Lange-Nielsen (JLN) syndrome due to compound heterozygous loss-of-function (LOF) KCNQ1 variants. We compared the effects of pharmacologic IKs block to those of genetic KCNQ1 ablation, using JLN cells, cells homozygous for the KCNQ1 LOF allele G643S, or siRNAs reducing KCNQ1 expression. We also studied the effects of two blockers of IKr, the other major cardiac repolarizing current, in the setting of pharmacologic or genetic ablation of KCNQ1: moxifloxacin, associated with a very low risk of drug-induced long QT, and dofetilide, a high-risk drug. In control cells, a small IKs was readily recorded but the pharmacologic IKs block produced no change in action potential duration at 90% repolarization (APD90). In contrast, in cells with genetic ablation of KCNQ1 (JLN), baseline APD90 was markedly prolonged compared with control cells (469 ± 20 vs. 310 ± 16 ms). JLN cells displayed increased sensitivity to acute IKr block: the concentration (μM) of moxifloxacin required to prolong APD90 100 msec was 237.4 [median, interquartile range (IQR) 100.6-391.6, n = 7] in population cells vs. 23.7 (17.3-28.7, n = 11) in JLN cells. In control cells, chronic moxifloxacin exposure (300 μM) mildly prolonged APD90 (10%) and increased IKs, while chronic exposure to dofetilide (5 nM) produced greater prolongation (67%) and no increase in IKs. However, in the siRNA-treated cells, moxifloxacin did not increase IKs and markedly prolonged APD90.
Conclusion: Our data strongly suggest that KCNQ1 expression modulates baseline cardiac repolarization, and the response to IKr block, through mechanisms beyond simply generating IKs.
Competing Interests: Conflict of interest: All authors report no conflict of interest.
(Published by Oxford University Press on behalf of the European Society of Cardiology 2024.)
التعليقات: Comment in: Cardiovasc Res. 2024 May 29;120(7):673-674. doi: 10.1093/cvr/cvae074. (PMID: 38630861)
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معلومات مُعتمدة: R00 HG010904 United States NH NIH HHS; P30 DK058404 United States DK NIDDK NIH HHS; P30 CA068485 United States CA NCI NIH HHS; R00 HG010904 United States HG NHGRI NIH HHS; 23CDA1048873 American Heart Association; R35 GM150465 United States GM NIGMS NIH HHS; Heart Rhythm Society
فهرسة مساهمة: Keywords: KCNQ1; IKr; IKs; Long QT; Repolarization reserve
المشرفين على المادة: 0 (KCNQ1 Potassium Channel)
0 (KCNQ1 protein, human)
U188XYD42P (Moxifloxacin)
R4Z9X1N2ND (dofetilide)
0 (Phenethylamines)
0 (Sulfonamides)
0 (Potassium Channel Blockers)
0 (Fluoroquinolones)
تواريخ الأحداث: Date Created: 20240305 Date Completed: 20240529 Latest Revision: 20240701
رمز التحديث: 20240701
مُعرف محوري في PubMed: PMC11135641
DOI: 10.1093/cvr/cvae042
PMID: 38442735
قاعدة البيانات: MEDLINE
الوصف
تدمد:1755-3245
DOI:10.1093/cvr/cvae042