© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Sustained activation of nuclear factor kappa B and activator protein 1 in chronic heart failure
aMedizinische Universitätsklinik Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany
bMedizinische Poliklinik der Universität Würzburg, Würzburg, Germany
* Corresponding author. Tel.: +49-931-201-36127; fax: +49-931-201-36131. s.frantz{at}mail.uni-wuerzburg.de
Objective: Innate immune response proteins such as inflammatory cytokines, inducible nitric oxide synthase, and toll like receptors are implicated in myocardial depression and left ventricular (LV) remodeling after myocardial infarction (MI). Although all these innate immunity proteins share the downstream activation of the transcription factor NF-
B (nuclear factor kappa B) and activator protein 1 (AP-1), the involvement of NF-B and AP-1 in LV remodeling has not been demonstrated so far. Methods and results: Nuclear translocation of NF-B and AP-1 was studied by electrophoretic mobility shift assays and ELISA 10 weeks after large experimental MI in rats, the chronic phase of LV remodeling. In the non-infarcted myocardium of MI rats, NF-B and AP-1 were significantly activated (2.5-fold) as compared to sham-operated animals. Immunohistochemistry demonstrated NF-B activation mainly in cardiac myocytes. Treatment with the ACE (angiotensin converting enzyme) inhibitor trandolapril led to a further 2-fold increase in the activation of NF-B and AP-1 when compared to placebo-treated animals with the same MI size (P<0.001). Human failing hearts explanted at the time of heart transplantation exhibited marked nuclear translocation of NF-B in cardiac myocytes when compared to control hearts. NF-B as well as AP-1 were both significantly activated in congestive heart failure due to ischemic or dilated cardiomyopathy. Conclusion: In experimental and human heart failure, both NF-B and AP-1 are chronically activated in cardiac myocytes. These findings suggest an important involvement of NF-B and AP-1 in the cardiac remodeling process.
KEYWORDS Cytokines; Immunology; Infarction; Remodeling
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