Myoglobin Protects the Heart from Inducible Nitric-oxide Synthase (iNOS)-mediated Nitrosative Stress

The role of inducible nitric-oxide synthase (iNOS) in the pathogenesis of heart failure is still a matter of controversy. In contrast to early reports favoring a contribution of iNOS because of the negative inotropic and apoptotic potential of NO, more recent clinical and experimental data question...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-06, Vol.278 (24), p.21761-21766
Main Authors: Gödecke, Axel, Molojavyi, Andre, Heger, Jacqueline, Flögel, Ulrich, Ding, Zhaoping, Jacoby, Christoph, Schrader, Jürgen
Format: Article
Language:English
Subjects:
Animals
Heart - physiology
Hypertrophy
Magnetic Resonance Imaging
Mice
Mice, Transgenic
Models, Chemical
Myocardium - enzymology
Myocardium - metabolism
Myoglobin - metabolism
Myoglobin - physiology
Nitric Oxide - metabolism
Nitric Oxide Synthase - metabolism
Nitric Oxide Synthase Type II
Nitrosation
Perfusion
Pressure
Sodium Chloride - pharmacology
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Summary:The role of inducible nitric-oxide synthase (iNOS) in the pathogenesis of heart failure is still a matter of controversy. In contrast to early reports favoring a contribution of iNOS because of the negative inotropic and apoptotic potential of NO, more recent clinical and experimental data question a causative role. Here we report that transgenic mice with cardiac specific iNOS-overexpression and concomitant myoglobin-deficiency (tg-iNOS+/myo–/–) develop signs of heart failure with cardiac hypertrophy, ventricular dilatation, and interstitial fibrosis. In addition, reactivation of the fetal gene expression program typical for heart failure occurs. The structural and molecular changes are accompanied by functional depression such as reduced contractility, ejection fraction, and cardiac energetics. Our findings indicate that excessive cardiac NO formation can cause heart failure; however, under normal circumstances myoglobin constitutes the important barrier that efficiently protects the heart from nitrosative stress.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M302573200