Copyright © 2006, European Society of Cardiology
Myocardial expression of Murf-1 and MAFbx after induction of chronic heart failure: Effect on myocardial contractility
aUniversity Leipzig-Heart Center Leipzig, Department of Cardiology, Leipzig, Germany
bDepartment of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
cInstitute of Anesthesiology and Operative Intensive Medicine; University Mannheim, Germany
dDepartment of Medicine III, Martin-Luther University Halle-Wittenberg, Halle, Germany
* Corresponding author. Universität Leipzig, Herzzentrum, Klinik für Innere Medizin / Kardiologie, Strümpellstrasse 39, D-04289 Leipzig, Germany. Tel.: +49 341 865 1671; fax: +49 341 865 1461. Email address: adav{at}medizin.uni-leipzig.de
Objective: In chronic heart failure (CHF) the myocardial expression of the inflammatory cytokine tumor necrosis factor alpha (TNF-
), which is thought to contribute to myocardial remodeling, was found to be increased. However, it is unknown whether the E3-ubiquitin ligases MAFbx and Murf-1 are involved in this remodeling process and whether their expression is regulated by TNF-.
Methods: Rats underwent ligation of the left coronary artery to induce CHF or were sham-operated. The expression of MAFbx/Murf-1 and troponin I was analyzed by RT-PCR and Western blotting in the non-infarcted area of the left ventricle. In cell culture experiments the potency of TNF- to stimulate Murf-1/MAFbx expression, the intracellular signaling pathway, and the involvement of the E3-ligases for the impairment of contractility were assessed.
Results: In CHF the myocardial expression of TNF- was elevated 3.1-fold as compared to control. This was associated with a 4.5-fold and 2.7-fold increase in MAFbx and Murf-1 expression, respectively. A positive correlation between TNF- and the expression of MAFbx or Murf-1 was evident. In neonatal rat cardiomyocytes, TNF- induced the expression of MAFbx through p38MAPK-dependent pathways, whereas the induction of Murf-1 required the activation of the p42/44 MAPK pathway. Exposure of cardiomyocytes to TNF- resulted in troponin I ubiquitinylation, subsequent degradation, and a decline in contractility. This was completely abrogated by siRNAs against Murf-1/MAFbx.
Conclusion: TNF-, which is increasingly expressed in CHF, induces troponin I degradation through a MAFbx/Murf-1-dependent pathway. This was associated with an impairment of contractility and might be one mechanism involved in the adverse remodeling process in CHF.
KEYWORDS Heart failure; Gene expression; Cytokines; Myocytes; Protein catabolism; Ubiquitin proteasome system
1 Both authors contributed equally to this work.