MicroRNA-155 inhibition attenuates endoplasmic reticulum stress-induced cardiomyocyte apoptosis following myocardial infarction via reducing macrophage inflammation
MicroRNA-155 inhibition attenuates endoplasmic reticulum stress-induced cardiomyocyte apoptosis following myocardial infarction via reducing macrophage inflammation
复制标题
MicroRNA-155 抑制通过减少巨噬细胞炎症来减轻心肌梗死后内质网应激诱导的心肌细胞凋亡
DOI：
10.1016/j.ejphar.2019.172449
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发表时间：
2019-08-15
影响因子：
5
通讯作者：
Zhang, Guo-Gang
中科院分区：
文献类型：
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作者：
Hu, Juan;Huang, Cong-Xin;Zhang, Guo-Gang
内质网应激（ERS）诱导的心肌细胞凋亡在心肌梗死（MI）后的病理过程中起重要作用。表达microRNA-155（miR-155）的巨噬细胞介导心脏炎症、纤维化和肥大。因此，我们使用小鼠模型、脂多糖（LPS）诱导的大鼠骨髓源性巨噬细胞（BMDM）和缺氧诱导的新生大鼠心肌细胞（NRCM）来研究miR-155是否调节MI后ERS诱导的心肌细胞凋亡。在体内，MI组的miR-155水平显著高于假手术组。MI增加了巨噬细胞浸润、核因子-κ B（NF-κ B）活化、ERS诱导的凋亡和SOCS 1表达，所有这些都被miR-155 Ekrosomir减弱，但SOCS 1表达除外。此外，MI后心功能不全通过miR-155抑制显著改善。在体外，LPS上调BMDM中的miR-155表达，并且miR-155 Atomir降低LPS诱导的巨噬细胞炎症和NF-κ B通路活化，但增加SOCS 1的表达。缺氧增加了NRCM中NF-κ B通路的激活、ERS标记物的表达和凋亡。有趣的是，来自LPS诱导的巨噬细胞的条件培养基与miR-155阿戈米组合降低，而miR-155阿戈米增加了NRCM中的缺氧诱导效应。miR-155 agomir的作用通过抑制心肌细胞中的NF-κ B通路而逆转。此外，在LPS诱导的巨噬细胞中，SOCS 1敲低促进了缺氧诱导的NRCM中NF-κ B通路活化和ERS诱导的心肌细胞凋亡，但miR-155 Eschomir处理显著降低了SOCS 1-siRNA诱导的效应。这些数据表明，miR-155抑制通过SOCS 1/NF-κ B途径减少巨噬细胞炎症，从而减弱MI后ERS诱导的心肌细胞凋亡。
Endoplasmic reticulum stress (ERS)-induced cardiomyocyte apoptosis plays an important role in the pathological process following myocardial infarction (MI). Macrophages that express microRNA-155 (miR-155) mediate cardiac inflammation, fibrosis, and hypertrophy. Therefore, we investigated if miR-155 regulates ERS-induced cardiomyocyte apoptosis after MI using a mouse model, lipopolysaccharide (LPS)-induced rat bone marrow derived macrophages (BMDMs) and hypoxia-induced neonatal rat cardiomyocytes (NRCMs). In vivo, miR-155 levelswere significantly higher in the MI group compared to the sham group. MI increasedmacrophage infiltration, nuclear factor-kappa B (NF-kappa B) activation, ERS induced-apoptosis, and SOCS1 expression, all of which were attenuated by the miR-155 antagomir, with the exception of SOCS1 expression. Additionally, post-MI cardiac dysfunction was significantly improved by miR-155 inhibition. In vitro, LPS upregulated miR-155 expression in BMDMs, and the miR-155 antagomir decreased LPS-induced macrophage inflammation and NF-kappa B pathway activation, but increased expression of SOCS1. Hypoxia increased NF-kappa B pathway activation, ERS marker expression, and apoptosis in NRCMs. Interestingly, conditioned medium from LPS-induced macrophages in combination with the miR-155 antagomir decreased, while the miR-155 agomir increased, the hypoxia-induced effects in NRCM's. The miR-155 agomir effects were reversed by inhibiting the NF-kappa B pathway in cardiomyocytes. Moreover, SOCS1 knockdown in LPS-induced macrophages promoted NF-kappa B pathway activation and ERS-induced cardiomyocyte apoptosis in the hypoxia-induced NRCMs, but the SOCS1-siRNA-induced effects were markedly decreased by miR-155 antagomir treatment. These data suggest that miR-155 inhibition attenuates ERS-induced cardiomyocyte apoptosis after MI via reducing macrophage inflammation through the SOCS1/NF-kappa B pathway.