Inhibition of MyD88 by a novel inhibitor reverses two-thirds of the infarct area in myocardial ischemia and reperfusion injury
Inhibition of MyD88 by a novel inhibitor reverses two-thirds of the infarct area in myocardial ischemia and reperfusion injury
复制标题
新型抑制剂抑制 MyD88 可逆转心肌缺血和再灌注损伤中三分之二的梗塞面积
DOI：
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发表时间：
2020
影响因子：
2.2
通讯作者：
Ping Zhou
中科院分区：
文献类型：
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作者：
Yan Miao;Zuochuan Ding;Zhimiao Zou;Yang Yang;Min Yang;Xiaoqian Zhang;Zeyang Li;Liang Zhou;Limin Zhang;Xue Zhang;Dunfeng Du;Fengchao Jiang;Ping Zhou
Cardiomyocytes, macrophages, and fibroblasts play important roles in inflammation and repair during myocardial ischemia/reperfusion injury (MIRI). Myeloid differentiation primary response 88 (MyD88) is upregulated in immunocytes, cardiomyocytes, and fibroblasts during MIRI. MyD88 induces the secretion of proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α), while fibroblasts are recruited and activated to mediate cardiac remodeling. The aim of this study was to assess the anti-MIRI effect and mode of action of the novel MyD88 inhibitor TJ-M2010-5. We synthesized TJ-M2010-5 and identified its target by co-immunoprecipitation, after which we established a murine MIRI model and tested the protective effect of TJ-M2010-5 by immunohistochemistry, flow cytometry, real-time PCR, and western blotting. Neonatal rat cardiomyocytes subjected to anoxia/reoxygenation were also isolated and their supernatants used to stimulate cardiac macrophagocytes and fibroblasts in vitro. MyD88 was found upregulated during the early and late phases after MIRI. The MyD88 inhibitor considerably improved cardiac function, reduced cardiomyocyte apoptosis, reduced IL-1β, IL-6, and TNF-α secretion, and inhibited CD80+CD86+MHCII+ macrophage and fibroblast migration. Moreover, TJ-M2010-5 markedly inhibited Toll-like receptor/MyD88 signaling in vivo and in vitro. Thus, our findings highlight TJ-M2010-5 as a potential therapeutic agent for MIRI treatment.
