Oxidative Stress Induced Ventricular Arrhythmia and Impairment of Cardiac Function in <i>Nos1ap</i> Deleted Mice

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Author(s)

    • Sugiyama Koji
    • Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University|Department of Cardiovascular Medicine, Tokyo Medical and Dental University School of Medicine
    • Sasano Tetsuo
    • Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University|Department of Cardiovascular Medicine, Tokyo Medical and Dental University School of Medicine|Department of Biofunctional Informatics, Tokyo Medical and Dental University School of Health Care Sciences
    • Kurokawa Junko
    • Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University
    • Takahashi Kentaro
    • Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University|Department of Cardiovascular Medicine, Tokyo Medical and Dental University School of Medicine
    • Okamura Tadashi
    • Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine|Section of Animal Models, Department of Infectious Disease, Research Institute, National Center for Global Health and Medicine
    • Kato Norihiro
    • Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine
    • Isobe Mitsuaki
    • Department of Cardiovascular Medicine, Tokyo Medical and Dental University School of Medicine
    • Furukawa Tetsushi
    • Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University

Abstract

Genome-wide association study has identified that the genetic variations at <i>NOS1AP</i> (neuronal nitric oxide synthase-1 adaptor protein) were associated with QT interval and sudden cardiac death (SCD). However, the mechanism linking a genetic variant of <i>NOS1AP</i> and SCD is poorly understood. We used <i>Nos1ap</i> knockout mice (<i>Nos1ap</i><sup>-/-</sup>) to determine the involvement of <i>Nos1ap</i> in SCD, paying special attention to oxidative stress.<br>At baseline, a surface electrocardiogram (ECG) and ultrasound echocardiography (UCG) showed no difference between <i>Nos1ap</i><sup>-/-</sup> and wild-type (WT) mice. Oxidative stress was induced by a single injection of doxorubicin (Dox, 25 mg/kg). After Dox injection, <i>Nos1ap</i><sup>-/-</sup> showed significantly higher mortality than WT (93.3 versus 16.0% at day 14, <i>P</i> < 0.01). ECG showed significantly longer QTc in <i>Nos1ap</i><sup>-/-</sup> than WT, and UCG revealed significant reduction of fractional shortening (%FS) only in <i>Nos1ap</i><sup>-/-</sup> after Dox injection. Spontaneous ventricular tachyarrhythmias were documented by telemetry recording after Dox injection only in <i>Nos1ap</i><sup>-/-</sup>. <i>Ex vivo</i> optical mapping revealed that the action potential duration (APD)<sub>90</sub> was prolonged at baseline in <i>Nos1ap</i><sup>-/-</sup>, and administration of Dox lengthened APD<sub>90</sub> more in <i>Nos1ap</i><sup>-/-</sup> than in WT. The expression of Bnp and the H<sub>2</sub>O<sub>2</sub> level were higher in <i>Nos1ap</i><sup>-/-</sup> after Dox injection. <i>Nos1ap</i><sup>-/-</sup> showed a reduced amplitude of calcium transient in isolated cardiomyocytes after Dox injection. Administration of the antioxidant N-acetyl-L-cysteine significantly reduced mortality of <i>Nos1ap</i><sup>-/-</sup> by Dox injection, accompanied by prevention of QT prolongation and a reduction in %FS.<br>Although <i>Nos1ap</i><sup>-/-</sup> mice have apparently normal hearts, oxidative stress evokes ventricular tachyarrhythmia and heart failure, which may cause sudden cardiac death.

Journal

  • International Heart Journal

    International Heart Journal 57(3), 341-349, 2016

    International Heart Journal Association

Codes

  • NII Article ID (NAID)
    130005153706
  • Text Lang
    ENG
  • ISSN
    1349-2365
  • Data Source
    J-STAGE 
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