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Adams, V. et al.

Adams, Linke, Wisloff, D??ring, Erbs, Kr??nkel, Witt, Labeit, M??ller-Werdan, Schuler, Hambrecht,

Myocardial expression of Murf-1 and MAFbx after induction of chronic heart failure: Effect on myocardial contractility.

OBJECTIVE: In chronic heart failure (CHF) the myocardial expression of the inflammatory cytokine tumor necrosis factor alpha ( TNF-alpha), 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-alpha. 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-alpha 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-alpha 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-alpha and the expression of MAFbx or Murf-1 was evident. In neonatal rat cardiomyocytes, TNF-alpha 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-alpha resulted in troponin I ubiquitinylation, subsequent degradation, and a decline in contractility. This was completely abrogated by siRNAs against Murf-1/ MAFbx. CONCLUSION: TNF-alpha, 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.[1]

References

Myocardial expression of Murf-1 and MAFbx after induction of chronic heart failure: Effect on myocardial contractility. Adams, V., Linke, A., Wisloff, U., D??ring, C., Erbs, S., Kr??nkel, N., Witt, C.C., Labeit, S., M??ller-Werdan, U., Schuler, G., Hambrecht, R. Cardiovasc. Res. (2007) [Pubmed]

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