Oxidative Stress Induced Ventricular Arrhythmia and Impairment of Cardiac Function in Nos1ap Deleted Mice

Int Heart J. 2016 May 25;57(3):341-9. doi: 10.1536/ihj.15-471. Epub 2016 May 9.

Abstract

Genome-wide association study has identified that the genetic variations at NOS1AP (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 NOS1AP and SCD is poorly understood. We used Nos1ap knockout mice (Nos1ap(-/-)) to determine the involvement of Nos1ap in SCD, paying special attention to oxidative stress.At baseline, a surface electrocardiogram (ECG) and ultrasound echocardiography (UCG) showed no difference between Nos1ap(-/-) and wild-type (WT) mice. Oxidative stress was induced by a single injection of doxorubicin (Dox, 25 mg/kg). After Dox injection, Nos1ap(-/-) showed significantly higher mortality than WT (93.3 versus 16.0% at day 14, P < 0.01). ECG showed significantly longer QTc in Nos1ap(-/-) than WT, and UCG revealed significant reduction of fractional shortening (%FS) only in Nos1ap(-/-) after Dox injection. Spontaneous ventricular tachyarrhythmias were documented by telemetry recording after Dox injection only in Nos1ap(-/-). Ex vivo optical mapping revealed that the action potential duration (APD)90 was prolonged at baseline in Nos1ap(-/-), and administration of Dox lengthened APD90 more in Nos1ap(-/-) than in WT. The expression of Bnp and the H2O2 level were higher in Nos1ap(-/-) after Dox injection. Nos1ap(-/-) 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 Nos1ap(-/-) by Dox injection, accompanied by prevention of QT prolongation and a reduction in %FS.Although Nos1ap(-/-) mice have apparently normal hearts, oxidative stress evokes ventricular tachyarrhythmia and heart failure, which may cause sudden cardiac death.

MeSH terms

  • Acetylcysteine / pharmacology*
  • Adaptor Proteins, Signal Transducing / genetics*
  • Animals
  • Antioxidants / pharmacology
  • Death, Sudden, Cardiac* / etiology
  • Death, Sudden, Cardiac* / prevention & control
  • Electrocardiography / methods
  • Heart Failure* / complications
  • Heart Failure* / metabolism
  • Heart Failure* / prevention & control
  • Mice
  • Mice, Knockout
  • Models, Cardiovascular
  • Oxidative Stress / drug effects*
  • Polymorphism, Single Nucleotide
  • Tachycardia, Ventricular* / complications
  • Tachycardia, Ventricular* / metabolism
  • Tachycardia, Ventricular* / prevention & control

Substances

  • Adaptor Proteins, Signal Transducing
  • Antioxidants
  • Nos1ap protein, mouse
  • Acetylcysteine