Key result
Synthetic bacterial DNA induces TLR9-dependent inflammation and loss of myocardial contractility in mice.
Bacterial DNA induces myocardial inflammation and depresses cardiomyocyte contractility through a TLR9 and iNOS-dependent pathway, highlighting a potential mechanism for sepsis-induced cardiac dysfunction.
May implicate TLR9 in sepsis cardiomyopathy; leaves open whether pathway inhibition improves human outcomes.
AIMS: 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 AND RESULTS: 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. 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)-1beta, IL-6, inducible nitric oxide synthase (iNOS), and nuclear factor kappaB 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.
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Knuefermann et al. (2008) studied Myocardial inflammation and cardiac contractility. Synthetic bacterial DNA (CpG-ODN) vs. TLR9-deficient mice / specific iNOS inhibitor was evaluated on Myocardial contractility and markers of inflammation/signalling. Synthetic bacterial DNA (CpG-ODN) induced a robust inflammatory response and a TLR9-dependent loss of sarcomeric shortening in wild-type mice, which was absent in TLR9-deficient mice.
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