Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death.
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.
Mungrue
Imran N
IN
Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada.
Gros
Robert
R
You
Xiaomang
X
Pirani
Asif
A
Azad
Azar
A
Csont
Tamas
T
Schulz
Richard
R
Butany
Jagdish
J
Stewart
Duncan J
DJ
Husain
Mansoor
M
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
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