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Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 14, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn011
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Bacterial DNA induces myocardial inflammation and reduces cardiomyocyte contractility: Role of Toll-like receptor 9

Pascal Knuefermann, MD1,*,, Markus Schwederski, PhD1,*, Markus Velten, MD1, Peter Krings, MD1, Heidi Ehrentraut, PhD1, Myriam Rüdiger2, Olaf Boehm, MD1, Klaus Fink, MD3, Ulrike Dreiner, MD2, Christian Grohé, MD5, Andreas Hoeft, MD1, Georg Baumgarten, MD1, Alexander Koch, MD4, Kai Zacharowski, MD PhD4 and Rainer Meyer, PhD2

1 Department for Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Germany
2 Institute of Physiology II, University Hospital Bonn, Germany
3 Department of Pharmacology and Toxicology, University Hospital Bonn, Germany
4 Molecular Cardioprotection & Inflammation Group, Department of Anaesthesia, Bristol Royal Infirmary, Bristol, UK
5 Department of Internal Medicine, University Hospital Bonn, Germany

Corresponding author: Pascal Knuefermann, MD Department for Anesthesiology and Intensive Care Medicine University Hospital Bonn Sigmund-Freud-Strasse 25, 53105 Bonn, Germany phone: 49-228-2871-4110; FAX: 49-228-2871-4115 E-Mail: Pascal.Knuefermann{at}ukb.uni-bonn.de

Aim: Myocardial function is severely compromised during sepsis. Several underlying mechanisms have been proposed. The innate immune system, i.e. Toll-like receptor (TLR) 2 and 4, significantly contributes to cardiac dysfunction. Little is known regarding TLR9 and its pathogenic ligand bacterial DNA in the myocardium. We therefore studied the role of TLR9 in myocardial inflammation and cardiac contractility.

Methods: Wild-type (WT, C57BL/6) and TLR9-deficient (TLR9-D) mice and isolated cardiomyocytes were challenged with synthetic bacterial DNA (CpG-ODN). Myocardial contractility as well as markers of inflammation/signalling were determined.

Results: Isolated cardiomyocytes incorporated fluorescence-marked CpG-ODN. In WT mice, CpG-ODN caused a robust response in hearts demonstrated by increased levels of tumour necrosis factor (TNF-{alpha}), interleukin (IL)-1β, IL-6, inducible nitric oxide synthase (iNOS), and nuclear factor {kappa}B activity. This inflammatory response was absent in TLR9-D mice. Under similar conditions, contractility measurements of isolated ventricular cardiomyocytes demonstrated a TLR9-dependent loss of sarcomeric shortening after CpG-ODN exposure. This observation was iNOS dependent as the application of a specific iNOS inhibitor reversed sarcomeric shortening to normal levels.

Conclusion: Our data suggest that bacterial DNA contributes to myocardial cytokine production and loss of cardiomyocyte contractility via TLR9.

KEYWORDS sepsis; contractile function; infection/inflammation; cell culture/isolation; cardiomyocytes

Time for primary review: 24

* These two authors contributed equally to this work


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