title: 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.
authors.affiliation: Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University.
authors.forename: Koji
authors.initials: K
authors.lastname: Sugiyama
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Sasano
authors.forename: Junko
authors.initials: J
authors.lastname: Kurokawa
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takahashi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okamura
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kato
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Furukawa
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000517:prevention & control; D004562:Electrocardiography / Q000379:methods; D006333:Heart Failure / Q000150:complications / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D018384:Oxidative Stress / Q000187:drug effects*; D020641:Polymorphism, Single Nucleotide; D017180:Tachycardia, Ventricular / Q000150:complications / Q000378:metabolism / Q000517:prevention & control
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; C110667:Nos1ap protein, mouse; D000111:Acetylcysteine