Dong Rui-qing, Wang Ze-feng, Zhao Can, Gu Hai-rong, Hu Zhuo-wei, Xie Jing, Wu Yong-quan
Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Molecular Immunology and Pharmacology Laboratory, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
J Cardiovasc Pharmacol Ther. 2015 Jan;20(1):84-92. doi: 10.1177/1074248414539564. Epub 2014 Jun 20.
Toll-like receptor 4 participates in the process of acute heart injury. The underlying mechanisms of its protection are multifactorial, but we hypothesized that toll-like receptor-mediated autophagy control plays a vital role. The purpose of this study was to clarify the effect of autophagy on cardiac fibrosis.
Cardiac fibrosis was induced by subcutaneous isoproterenol (ISO) injection, and rapamycin was simultaneously administered orally for 14 days. Animal echocardiography was then used to evaluate the success of the cardiac fibrosis model, and the mice were killed after the echocardiography examination.
Toll-like receptor 4 knockout (TLR4 KO) mice had better heart function than did wild-type (WT) mice (P < .05). Rapamycin treatment reduced the left ventricular ejection fraction to 23.5% (P < .05), and the collagen volume fraction of the ISO and ISO plus rapamycin groups was 5.9% and 25.9%, respectively, in TLR4 KO mice. Compared with the WT mice, Beclin 1 and autophagy were downregulated in TLR4 KO mice (P < .05); however, the ISO plus rapamycin group had higher autophagy activity than did the ISO group in TLR4 KO mice (P < .05).
Our results suggest that TLR4 KO-induced cardioprotection against ISO-induced cardiac fibrosis is associated with reduced autophagy induction. Cardiac fibroblast autophagy participates in its own activation. The moderate inhibition of autophagic activity may be a new strategy for treating cardiac fibrosis.
Toll样受体4参与急性心脏损伤过程。其保护作用的潜在机制是多因素的，但我们推测Toll样受体介导的自噬控制起着至关重要的作用。本研究的目的是阐明自噬对心脏纤维化的影响。
通过皮下注射异丙肾上腺素（ISO）诱导心脏纤维化，并同时口服雷帕霉素14天。然后使用动物超声心动图评估心脏纤维化模型是否成功，超声心动图检查后处死小鼠。
Toll样受体4基因敲除（TLR4 KO）小鼠的心功能优于野生型（WT）小鼠（P < 0.05）。雷帕霉素治疗使TLR4 KO小鼠的左心室射血分数降至23.5%（P < 0.05），ISO组和ISO加雷帕霉素组的胶原容积分数分别为5.9%和25.9%。与WT小鼠相比，TLR4 KO小鼠中Beclin 1和自噬下调（P < 0.05）；然而，在TLR4 KO小鼠中，ISO加雷帕霉素组的自噬活性高于ISO组（P < 0.05）。
我们的结果表明，TLR4基因敲除诱导的对ISO诱导的心脏纤维化的心脏保护作用与自噬诱导减少有关。心脏成纤维细胞自噬参与其自身的激活。适度抑制自噬活性可能是治疗心脏纤维化的一种新策略。
