In Vivo TLR9 Inhibition Attenuates CpG-Induced Myocardial Dysfunction

• Published in: Mediators of Inflammation Vol. 2013; no. 2013; pp. 1 - 9
• Main Authors: Baumgarten, Georg, Meyer, Rainer, Knuefermann, Pascal, Boehm, Olaf, Hoeft, Andreas, Brill, C., Kokalova, A., Markowski, P., van der Giet, M., Gielen, V.
• Format: Journal Article
• Language: English
• Published: Cairo, Egypt Hindawi Limiteds 01.01.2013; Hindawi Puplishing Corporation; Hindawi Publishing Corporation; Hindawi Limited; Wiley
• Subjects: Animals; Cardiomyopathy; Cell Line; Chloroquine - pharmacology; Health aspects; Heart - drug effects; Heart diseases; Interleukin-1beta - metabolism; Interleukin-6 - metabolism; Male; Mice; Mice, Inbred C57BL; Myocardium - metabolism; Myocardium - pathology; Oligodeoxyribonucleotides - toxicity; Physiological aspects; Sepsis; Toll-Like Receptor 9 - antagonists & inhibitors; Toll-Like Receptor 9 - metabolism; Toll-like receptors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0962-9351; 1466-1861
• DOI: 10.1155/2013/217297

The involvement of toll-like receptor 9 (TLR9), a receptor for bacterial DNA, in septic cardiac depression has not been clarified in vivo. Thus, the aim of the study was to test possible TLR9 inhibitors (H154-thioate, IRS954-thioate, and chloroquine) for their ability to protect the cardiovascular system in a murine model of CpG oligodeoxynucleotide- (ODN-) dependent systemic inflammation. Sepsis was induced by i.p. application of the TLR9 agonist 1668-thioate in C57BL/6 wild type (WT) and TLR9-deficient (TLR9-D) mice. Thirty minutes after stimulation TLR9 antagonists were applied i.v. Survival was monitored up to 18 h after stimulation. Cardiac mRNA expression of inflammatory mediators was analyzed 2 h and 6 h after stimulation with 1668-thioate and hemodynamic parameters were monitored at the later time point. Stimulation with 1668-thioate induced a severe sepsis-like state with significant drop of body temperature and significantly increased mortality in WT animals. Additionally, there was a time-dependent increase of inflammatory mediators in the heart accompanied by development of septic heart failure. These effects were not observed in TLR9-D mice. Inhibition of TLR9 by the suppressive ODN H154-thioate significantly ameliorated cardiac inflammation, preserved cardiac function, and improved survival. This suppressive ODN was the most efficient inhibitor of the tested substances.