MicroRNA-21 prevents excessive inflammation and cardiac dysfunction after myocardial infarction through targeting KBTBD7.
MicroRNA-21 prevents excessive inflammation and cardiac dysfunction after myocardial infarction through targeting KBTBD7.
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MicroRNA-21通过靶向KBTBD7预防心肌梗塞后的过度炎症和心脏功能障碍
DOI：
10.1038/s41419-018-0805-5
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发表时间：
2018-07-10
影响因子：
9
通讯作者：
Zhan Z
中科院分区：
文献类型：
--
作者：
Yang L;Wang B;Zhou Q;Wang Y;Liu X;Liu Z;Zhan Z
心肌梗死（MI）后损伤相关分子模式（DAMPs）引发的过度炎症是导致心功能不全和不良重构的原因，而炎症的微调机制仍有待充分阐明。MicroRNA-21（miR-21）已被证明在心血管疾病中起作用，而其在小鼠MI后的炎症反应和心脏功能中的作用仍然未知。在此，我们发现，在通过结扎冠状动脉左前降支建立的MI模型的早期炎症阶段，miR-21表达在心脏组织的边缘和梗死区显著增加。与WT小鼠相比，MiR-21敲除小鼠的存活率降低，心功能障碍更严重，MI后梗死和瘢痕面积增加。MiR-21基因敲除小鼠心脏组织中的炎性细胞因子（包括IL-1β、IL-6和TNF-α）水平显著升高，CD 11b+单核细胞/巨噬细胞浸润，炎性细胞因子表达水平升高。心肌梗死后心肌组织中高迁移率族蛋白B1（HMGB 1）和热休克蛋白60（HSP 60）大量释放。miR-21缺陷显著促进巨噬细胞中DAMPs触发的炎性细胞因子的产生，而miR-21过表达显著抑制炎性细胞因子的产生。从机制上讲，miR-21缺陷增强了MI后心脏组织和DAMP处理的巨噬细胞中p38和NF-κB信号的激活。MiR-21被发现直接靶向kelch重复序列和BTB（POZ）结构域7（KBTBD 7），其促进巨噬细胞中DAMP触发的炎症反应。此外，KBTBD 7与MKK 3/6相互作用并促进其活化，进而增强DAMPs诱导的下游p38和NF-κB信号通路的活化。因此，我们的研究结果表明，miR-21通过靶向KBTBD 7并抑制p38和NF-κB信号转导激活来减轻炎症、心功能障碍和MI后适应不良重构，这表明miR-21可能作为MI的新的潜在治疗靶点发挥作用。
The excessive inflammation triggered by damage-associated molecular patterns (DAMPs) after myocardial infarction (MI) is responsible for the development of cardiac dysfunction and adverse remodeling, while the mechanisms by which inflammation is fine tuned remain to be fully elucidated. MicroRNA-21 (miR-21) has been shown to function in cardiovascular diseases, while its role in inflammatory responses and cardiac function post MI in mice remains unknown. Here, we found that miR-21 expression was markedly increased in border and infarct areas of cardiac tissues during the early inflammatory phase of MI model established by ligating the left-anterior descending coronary artery. MiR-21 knockout mice had decreased survival rates, worse cardiac dysfunction, and increased infarct and scar areas after MI compared with WT mice. MiR-21 knockout mice showed significantly higher levels of inflammatory cytokines including IL-1β, IL-6, and TNF-α in cardiac tissues, as well as infiltration of CD11b+monocytes/macrophages with higher expression level of inflammatory cytokines. MI induced the great release of high mobility group protein B1 (HMGB1) and heat shock protein 60 (HSP60) in cardiac tissue. MiR-21 deficiency significantly promoted the inflammatory cytokine production triggered by DAMPs in macrophages, whereas, miR-21 overexpression markedly inhibited the inflammatory cytokine production. Mechanistically, miR-21 deficiency enhanced p38 and NF-κB signaling activation in cardiac tissue post MI and macrophages treated with DAMPs. MiR-21 was found to directly target kelch repeat and BTB (POZ) domain containing 7 (KBTBD7), which promoted DAMP-triggered inflammatory responses in macrophages. Furthermore, KBTBD7 interacted with MKK3/6 and promoted their activation, which in turn enhanced the activation of downstream p38 and NF-κB signaling induced by DAMPs. Therefore, our findings demonstrate that miR-21 attenuates inflammation, cardiac dysfunction, and maladaptive remodeling post MI through targeting KBTBD7 and inhibiting p38 and NF-κB signaling activation, suggesting that miR-21 may function as a novel potential therapeutic target for MI.
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DOI：
10.4049/jimmunol.1202012
发表时间：
2013-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Mannam P;Zhang X;Shan P;Zhang Y;Shinn AS;Zhang Y;Lee PJ
通讯作者：
Lee PJ
DAMP 诱导的自噬通过促进 TRAF6 泛素化促进缺血再灌注损伤肺部的炎症反应。
影响因子：
12.4
作者：
Liu X;Cao H;Li J;Wang B;Zhang P;Dong Zhang X;Liu Z;Yuan H;Zhan Z
通讯作者：
Zhan Z
影响因子：
5
作者：
Shinde, Arti V.;Frangogiannis, Nikolaos G.
通讯作者：
Frangogiannis, Nikolaos G.
影响因子：
4.4
作者：
Kang, Yanhua;Wang, Fang;Shi, Liyun
通讯作者：
Shi, Liyun
KBTBD7 是一种新型人类 BTB-kelch 蛋白，可激活 SRE 和 AP-1 的转录活性。
影响因子：
3.8
作者：
Hu, Junjian;Yuan, Wuzhou;Wu, Xiushan
通讯作者：
Wu, Xiushan