Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death

Imran N. Mungrue, Robert Gros, Xiaomang You, Asif Pirani, Azar Azad, Tamas Csont, Richard Schulz, Jagdish Butany, Duncan J. Stewartand, Mansoor Husain

Research output: Contribution to journalArticle

252 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)735-743
Number of pages9
JournalJournal of Clinical Investigation
Volume109
Issue number6
DOIs
Publication statusPublished - Jan 1 2002

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death'. Together they form a unique fingerprint.

  • Cite this

    Mungrue, I. N., Gros, R., You, X., Pirani, A., Azad, A., Csont, T., Schulz, R., Butany, J., Stewartand, D. J., & Husain, M. (2002). Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. Journal of Clinical Investigation, 109(6), 735-743. https://doi.org/10.1172/JCI0213265