title: Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death.
abstract: Increased inducible nitric oxide synthase (iNOS) expression is a component of the immune response and has been demonstrated in cardiomyocytes in septic shock, myocarditis, transplant rejection, ischemia, and dilated cardiomyopathy. To explore whether the consequences of such expression are adaptive or pathogenic, we have generated a transgenic mouse model conditionally targeting the expression of a human iNOS cDNA to myocardium. Chronic cardiac-specific upregulation of iNOS in transgenic mice led to increased production of peroxynitrite. This was associated with a mild inflammatory cell infiltrate, cardiac fibrosis, hypertrophy, and dilatation. While iNOS-overexpressing mice infrequently developed overt heart failure, they displayed a high incidence of sudden cardiac death due to bradyarrhythmia. This dramatic cardiac phenotype was rescued by specific attenuation of transgene activity. These data implicate cardiomyocyte iNOS overexpression as sufficient to cause cardiomyopathy, bradyarrhythmia, and sudden cardiac death.
authors.affiliation: Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Imran N
authors.initials: IN
authors.lastname: Mungrue
authors.forename: Robert
authors.initials: R
authors.lastname: Gros
authors.forename: Xiaomang
authors.initials: X
authors.lastname: You
authors.forename: Asif
authors.initials: A
authors.lastname: Pirani
authors.forename: Azar
authors.initials: A
authors.lastname: Azad
authors.forename: Tamas
authors.initials: T
authors.lastname: Csont
authors.forename: Richard
authors.initials: R
authors.lastname: Schulz
authors.forename: Jagdish
authors.initials: J
authors.lastname: Butany
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: Mansoor
authors.initials: M
authors.lastname: Husain
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001283:Atrioventricular Node / Q000166:cytology; D017630:Connexins / Q000378:metabolism; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004318:Doxycycline / Q000378:metabolism; D004452:Echocardiography; D015971:Gene Expression Regulation, Enzymologic; D006327:Heart Block / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D030421:Peroxynitrous Acid / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016019:Survival Analysis; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism; D000097003:Gap Junction alpha-5 Protein
chemical_list: D000110:Acetylcholinesterase; D017630:Connexins; D004318:Doxycycline; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D030421:Peroxynitrous Acid; D001616:beta-Galactosidase; D000097003:Gap Junction alpha-5 Protein; C496319:NOS2 protein, human; C496317:Nos2 protein, mouse