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 i mplicated in the pathology of spontaneous and antigen-induced autoimmu ne 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 w hether iNOS and NO are essential in the pathogenesis of autoimmune myo carditis. Methods and Results In the murine model of cardiac myosin-in duced myocarditis, we demonstrate that iNOS expression was elicited in inflammatory macrophages and in distinct cardiomyocytes. Autoimmune h eart disease was accompanied by formation of the NO reaction product n itrotyrosine in inflammatory macrophages as well as in cardiomyocytes. iNOS expression and nitrotyrosine formation were strictly dependent o n myocardial inflammation. Focal myocarditis was sufficient to induce nitrotyrosine formation throughout the whole heart muscle. Mice defect ive for the interferon regulatory transcription factor-1 (IRF-1(-/-)) after gene targeting failed to induce iNOS expression and nitrotyrosin e formation in the heart but developed cardiac myosin-induced myocardi tis at prevalence and severity similar to those of heterozygous litter mates (IRF-1(+/-)). Conclusions These data provide the first in vivo e vidence that iNOS expression and NO synthesis in macrophages and disti nct cardiomyocytes are elicited in experimental murine inflammatory he art disease. The transcription factor IRF-1 controls iNOS expression a nd 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 dev elopment of dilated cardiomyopathy and heart failure.