iNOS expression and nitrotyrosine formation in the myocardium in response to inflammation is controlled by the interferon regulatory transcription factor 1.
BACKGROUND
Production of NO by inducible NO synthase (iNOS) has been implicated in the pathology of spontaneous and antigen-induced autoimmune diseases, and iNOS is expressed in the myocardium of patients with heart failure. It is not clear whether inflammatory murine autoimmune heart disease, an experimental model for human postviral heart disease, is characterized by increased iNOS expression within the heart and whether iNOS and NO are essential in the pathogenesis of autoimmune myocarditis.


RESULTS
In the murine model of cardiac myosin-induced myocarditis, we demonstrate that iNOS expression was elicited in inflammatory macrophages and in distinct cardiomyocytes. Autoimmune heart disease was accompanied by formation of the NO reaction product nitrotyrosine in inflammatory macrophages as well as in cardiomyocytes. iNOS expression and nitrotyrosine formation were strictly dependent on myocardial inflammation. Focal myocarditis was sufficient to induce nitrotyrosine formation throughout the whole heart muscle. Mice defective for the interferon regulatory transcription factor-1 (IRF-1(-/-)) after gene targeting failed to induce iNOS expression and nitrotyrosine formation in the heart but developed cardiac myosin-induced myocarditis at prevalence and severity similar to those of heterozygous littermates (IRF-1(+/-)).


CONCLUSIONS
These data provide the first in vivo evidence that iNOS expression and NO synthesis in macrophages and distinct cardiomyocytes are elicited in experimental murine inflammatory heart disease. The transcription factor IRF-1 controls iNOS expression and NO synthesis in disease. Because autoimmune myocarditis can develop in animals lacking IRF-1, these mice will be useful to elucidate the link between iNOS expression in inflammatory heart disease and the development of dilated cardiomyopathy and heart failure.
Bachmaier
K
K
Amgen Institute, Ontario Cancer Institute, and Department of Medical Biophysics, University of Toronto, Canada.
Neu
N
N
Pummerer
C
C
Duncan
G S
GS
Mak
T W
TW
Matsuyama
T
T
Penninger
J M
JM
D000818:Animals; D015551:Autoimmunity; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D050856:Interferon Regulatory Factor-1; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009205:Myocarditis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D010750:Phosphoproteins / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014443:Tyrosine / Q000096:biosynthesis*
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D014157:Transcription Factors; D014443:Tyrosine; D019001:Nitric Oxide Synthase