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 APD
90 more in
Nos1ap-/- than in WT. The expression of Bnp and the H
2O
2 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.
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