Key result
After doxorubicin-induced oxidative stress, Nos1ap knockout mice showed significantly higher mortality than wild-type mice (93.3% vs 16.0%, P < 0.01) accompanied by lethal ventricular arrhythmias and impaired cardiac function.
Why the study?
Does Nos1ap deletion increase mortality, ventricular arrhythmias, and heart failure under oxidative stress in mice?
Does Nos1ap deletion increase mortality, ventricular arrhythmias, and heart failure under oxidative stress in mice?
Genetic deletion of Nos1ap in mice leads to increased mortality, ventricular tachyarrhythmias, and impaired cardiac function under oxidative stress, providing a mechanistic link between NOS1AP variants and sudden cardiac death.
Answers are grounded in this paper and cite their sources.
Nos1ap may mitigate doxorubicin cardiotoxicity in mice; leaves open its relevance to arrhythmia risk in patients.
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.
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Sugiyama et al. (2016) studied Oxidative stress-induced ventricular arrhythmia and sudden cardiac death. Nos1ap deletion (Nos1ap-/-) with Doxorubicin vs. Wild-type (WT) with Doxorubicin was evaluated on Mortality at day 14 (p=<0.01). After doxorubicin-induced oxidative stress, Nos1ap knockout mice showed significantly higher mortality than wild-type mice (93.3% vs 16.0%, P < 0.01) accompanied by lethal ventricular arrhythmias and impaired cardiac function.
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