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 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.
Gödecke
Axel
A
Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität, Postfach 101007, 40001 Düsseldorf, Germany. Axel.Goedecke@uni-duesseldorf.de
Molojavyi
Andre
A
Heger
Jacqueline
J
Flögel
Ulrich
U
Ding
Zhaoping
Z
Jacoby
Christoph
C
Schrader
Jürgen
J
D000818:Animals; D006321:Heart / Q000502:physiology; D006984:Hypertrophy; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D008956:Models, Chemical; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D009211:Myoglobin / Q000378:metabolism* / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D015538:Nitrosation; D010477:Perfusion; D011312:Pressure; D012965:Sodium Chloride / Q000494:pharmacology
D009211:Myoglobin; D009569:Nitric Oxide; D012965:Sodium Chloride; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse