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Impact of myocardial inflammation on cytosolic and mitochondrial creatine kinase activity and expression

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Abstract

The disturbance of myocardial energy metabolism has been discussed as contributing to the progression of heart failure. Little however is known about the cardiac mitochondrial/cytosolic energy transfer in murine and human inflammatory heart disease. We examined the myocardial creatine kinase (CK) system, which connects mitochondrial ATP-producing and cytosolic ATP-consuming processes and is thus of central importance to the cellular energy homeostasis. The time course of expression and enzymatic activity of mitochondrial (mtCK) and cytosolic CK (cytCK) was investigated in Coxsackievirus B3 (CVB3)-infected SWR mice, which are susceptible to the development of chronic myocarditis. In addition, cytCK activity and isoform expression were analyzed in biopsies from patients with chronic inflammatory heart disease (n = 22). Cardiac CVB3 titer in CVB3-infected mice reached its maximum at 4 days post-infection (pi) and became undetectable at 28 days pi; cardiac inflammation cumulated 14 days pi but persisted through the 28-day survey. MtCK enzymatic activity was reduced by 40% without a concurrent decrease in mtCK protein during early and acute MC. Impaired mtCK activity was correlated with virus replication and increased level of interleukine 1β (IL-1β), tumor necrosis factor α (TNFα), and elevated catalase expression, a marker for intracellular oxidative stress. A reduction in cytCK activity of 48% was observed at day 14 pi and persisted to day 28 pi. This restriction was caused by a decrease in cytCK subunit expression but also by direct inhibition of specific cytCK activity. CytCK activity and expression were also reduced in myocardial biopsies from enterovirus genome-negative patients with inflammatory heart disease. The decrease in cytCK activity correlated with the number of infiltrating macrophages. Thus, viral infection and myocardial inflammation significantly influence the myocardial CK system via restriction of specific CK activity and down-regulation of cytCK protein. These changes may contribute to the progression of chronic inflammatory heart disease and malfunction of the heart.

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Acknowledgment

This study was supported by the Deutsche Forschungsgemeinschaft, SFB-Transregio 19.

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Authors and Affiliations

  1. Centrum 11, Cardiology, Charité, University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany

    Linda Ebermann, Uwe Kühl, Nikias Siafarikas, Heinz-Peter Schultheiss & Andrea Dörner PhD

  2. Heart Center North Rhine-Westphalia, Dept. of Cardiology, Ruhr University of Bochum, Bad Oeynhausen, Germany

    Cornelia Piper

  3. Dept. of Molecular Pathology, Institute for Pathology, University Hospital Tübingen, Tübingen, Germany

    Karin Klingel

  4. Laboratory of Fundamental and Applied Bioenergetics, University Joseph Fourier, Grenoble, France

    Uwe Schlattner

  5. Dept. of Virology, Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany

    Heinz Zeichhardt

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  1. Linda Ebermann
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Correspondence to Andrea Dörner PhD.

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L. Ebermann and C. Piper have equally contributed to this work.

Returned for 1. Revision: 22 July 2008 1. Revision received: 20 October 2008

Returned for 2. Revision: 26 November 2008 2. Revision received: 3 December 2008

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Ebermann, L., Piper, C., Kühl, U. et al. Impact of myocardial inflammation on cytosolic and mitochondrial creatine kinase activity and expression. Basic Res Cardiol 104, 247–257 (2009). https://doi.org/10.1007/s00395-008-0773-5

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