给予Toll样受体9（TLR9）抑制剂可减轻小鼠心力衰竭的发生和发展。

Administration of a TLR9 Inhibitor Attenuates the Development and Progression of Heart Failure in Mice.

作者信息

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

机构信息

Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

出版信息

JACC Basic Transl Sci. 2019 May 22;4(3):348-363. doi: 10.1016/j.jacbts.2019.01.002. eCollection 2019 Jun.

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.

含有未甲基化胞嘧啶 - 磷酸 - 鸟苷基序的线粒体脱氧核糖核酸会刺激Toll样受体9，从而引发炎症和心力衰竭。一种名为E6446 [（6 - [3 - （吡咯烷 - 1 - 基）丙氧基] - 2 - （4 - [3 - （吡咯烷 - 1 - 基）丙氧基]苯基）苯并[d]恶唑]）的小分子化合物是心肌细胞中特异性的Toll样受体9抑制剂。在本研究中，我们发现E6446对预防和治疗小鼠压力超负荷诱导的心力衰竭具有有益作用。在手术前给药并在其后长期给药时，E6446可防止左心室扩张以及心脏功能障碍、纤维化和炎症的发展。此外，在心脏功能障碍出现后给药时，E6446减缓了心脏重塑的进程。因此，该抑制剂可能是治疗心力衰竭患者的新型治疗药物。