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

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.