Administration of a TLR9 inhibitor attenuates the development and progression of heart failure in mice

Hiromichi Ueda, Osamu Yamaguchi, Manabu Taneike, Yasuhiro Akazawa, Haruko Wada-Kobayashi, Ryuta Sugihara, Hiroki Yorifuji, Hiroyuki Nakayama, Shigemiki Omiya, Tomokazu Murakawa, Yasushi Sakata, Kinya Otsu

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Mitochondrial deoxyribonucleic acid, containing the unmethylated cytidine-phosphate-guanosine motif, stimulates Toll-like receptor 9 to induce inflammation and heart failure. A small chemical, E6446 [(6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole)], is a specific Toll-like receptor 9 inhibitor in cardiomyocytes. In this study, we showed that E6446 exerts beneficial effects for the prevention and treatment of pressure overload–induced heart failure in mice. When administered before the operation and chronically thereafter, E6446 prevented the development of left ventricular dilatation as well as cardiac dysfunction, fibrosis, and inflammation. Furthermore, when administered after the manifestation of cardiac dysfunction, E6446 slowed progression of cardiac remodeling. Thus, the inhibitor may be a novel therapeutic agent for treating patients with heart failure.

Original languageEnglish
Article number10
Pages (from-to)348-363
Number of pages16
JournalJACC: Basic to Translational Science
Issue number3
Early online date22 May 2019
Publication statusPublished - Jun 2019


  • Toll-like receptor 9
  • heart failure
  • mitochondria
  • pressure overload


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