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Acute DNase1 treatment improves left ventricular remodeling after myocardial infarction by disruption of free chromatin

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Abstract

Myocardial infarction (MI) leads to necrosis and uncontrolled release of cellular content. Binucleated and polyploid cardiomyocytes contain high amounts of chromatin, a DNA polymer of histones which are cytotoxic. We hypothesized that chromatin from necrotic cells accumulates in the non-perfused, ischemic infarct region, causing local high concentrations of cytotoxic histones, thereby potentiating damage to the heart after MI. The endonuclease DNase1 is capable of dispersing extracellular chromatin through linker DNA digestion which could lead to a decrease in local histone concentrations and cytotoxicity. It was confirmed that after permanent coronary artery ligation in mice, extracellular histones accumulated within the infarcted myocardium. In vitro, histones caused myocyte cytotoxicity. For protection against histone-mediated cytotoxicity after MI in vivo, DNase1 was administered within the first 6 h after induction. Indeed, DNase1 accumulation in the infarcted region of the heart was observed, as well as effective disruption of extracellular cytotoxic chromatin and subsequent reduction of high local histone concentrations. Functionally, acute DNase1 treatment resulted in significantly improved left ventricular remodeling in mice as measured by serial echocardiography, while mortality, infarct size and inflammatory parameters were unaffected. Notably, improved cardiomyocyte survival within the infarct region was observed and might account for the protective effects in acutely DNase1-treated animals. Disruption of extracellular cytotoxic chromatin within the infarcted heart by acute DNase1 treatment is a promising approach to protect myocytes from histone-induced cell death and subsequent left ventricular dysfunction after MI.

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Abbreviations

dsDNA:

Double-stranded DNA

NET:

Neutrophil extracellular trap

cfDNA:

Cell-free DNA

LDH:

Lactate dehydrogenase

PSR:

Picrosirius red

MI:

Myocardial infarction

MI/R:

Myocardial ischemia/reperfusion

H3-cit:

Histone H3 citrullination

ESM fraction:

Extracellular soluble myocardial fraction

DNase1:

Desoxyribonuclease 1

NRVM:

Neonatal rat ventricular myocytes

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Acknowledgments

We thank Charlotte Dienesch, Sandra Umbenhauer, and Hanna Siebert for technical assistance, Nicola Jones for critically reading the manuscript and Silvana Olivares-Florez for providing us with neonatal rat ventricular myocytes. This work was supported by a grant of the German Bundesministerium für Bildung und Forschung (BMBF01 EO1004) (G.E., S.F.).

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    Authors and Affiliations

    1. Comprehensive Heart Failure Center (CHCF), Universitätsklinikum Würzburg, Zinklesweg 10, 97078, Würzburg, Germany

      Benjamin Vogel, Hisahito Shinagawa, Ulrich Hofmann, Georg Ertl & Stefan Frantz

    2. Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Würzburg, Germany

      Benjamin Vogel, Hisahito Shinagawa, Ulrich Hofmann, Georg Ertl & Stefan Frantz

    3. Department of Cardiology and Vascular Medicine, Kitasato University, Minato, Japan

      Hisahito Shinagawa

    4. Universitätsklinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale), Germany

      Ulrich Hofmann & Stefan Frantz

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    B. Vogel and H. Shinagawa contributed equally.

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    Vogel, B., Shinagawa, H., Hofmann, U. et al. Acute DNase1 treatment improves left ventricular remodeling after myocardial infarction by disruption of free chromatin. Basic Res Cardiol 110, 15 (2015). https://doi.org/10.1007/s00395-015-0472-y

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