MicroRNA-146b-5p promotes atrial fibrosis in atrial fibrillation by repressing TIMP4.
MicroRNA-146b-5p promotes atrial fibrosis in atrial fibrillation by repressing TIMP4.
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MicroRNA-146b-5p通过抑制TIMP4促进心房颤动的心房纤维化。
DOI：
10.1111/jcmm.16985
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发表时间：
2021-11
影响因子：
5.3
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Ye Q;Liu Q;Ma X;Bai S;Chen P;Zhao Y;Bai C;Liu Y;Liu K;Xin M;Zeng C;Zhao C;Yao Y;Ma Y;Wang J
基质金属蛋白酶组织抑制因子（TIMP）/基质金属蛋白酶（MMP）的改变与胶原蛋白的上调在持续性心房颤动（AF）中起重要作用。miR-146 b-5 p的表达，其靶基因是TIMPs，本研究旨在探讨miR-146 b-5 p是否能够调控TIMP 4基因表达，以及miR-146 b-5 p在房颤心房纤维化中的作用。体外（hiPSC‐ aCM）-成纤维细胞共培养细胞模型。此外，使用心肌梗死（MI）小鼠模型来证实miR-146 b-5 p下调对心房纤维化的保护作用。miR-146 b-5 p在房颤犬的纤维化心房中表达上调，而TIMP 4表达下调。miR-146 b-5 p转染hiPSC-aCMs-成纤维细胞共培养细胞模型，通过调节TIMP 4/MMP 9介导的细胞外基质蛋白合成增加胶原合成。在MI小鼠模型中，miR-146 b-5 p表达的抑制降低了心脏纤维化的表型。在MI心脏的心肌细胞中，通过miR-146 b-5 p抑制，纤维化标志物MMP 9、TGFB 1和COL 1A 1显著下调，而TIMP 4显著上调（在mRNA和蛋白水平）。我们得出结论，在miR-146 b-5 p过表达的共培养细胞模型中，胶原纤维积聚在细胞外空间中。此外，miR-146 b-5 p的抑制可能成为预防心房纤维化的有效治疗方法。
Alteration of tissue inhibitors of matrix metalloproteinases (TIMP)/matrix metalloproteinases (MMP) associated with collagen upregulation has an important role in sustained atrial fibrillation (AF). The expression of miR‐146b‐5p, whose the targeted gene is TIMPs, is upregulated in atrial cardiomyocytes during AF. This study was to determine whether miR‐146b‐5p could regulate the gene expression of TIMP4 and the contribution of miRNA to atrial fibrosis in AF. Collagen synthesis was observed after miR‐146b‐5p transfection in human induced pluripotent stem cell‐derived atrial cardiomyocytes (hiPSC‐aCMs)‐fibroblast co‐culture cellular model in vitro. Furthermore, a myocardial infarction (MI) mouse model was used to confirm the protective effect of miR‐146b‐5p downregulation on atrial fibrosis. The expression level of miR‐146b‐5p was upregulated, while the expression level of TIMP4 was downregulated in the fibrotic atrium of canine with AF. miR‐146b‐5p transfection in hiPSC‐aCMs‐fibroblast co‐culture cellular model increased collagen synthesis by regulating TIMP4/MMP9 mediated extracellular matrix proteins synthesis. The inhibition of miR‐146b‐5p expression reduced the phenotypes of cardiac fibrosis in the MI mouse model. Fibrotic marker MMP9, TGFB1 and COL1A1 were significantly downregulated, while TIMP4 was significantly upregulated (at both mRNA and protein levels) by miR‐146b‐5p inhibition in cardiomyocytes of MI heart. We concluded that collagen fibres were accumulated in extracellular space on miR‐146b‐5p overexpressed co‐culture cellular model. Moreover, the cardiac fibrosis induced by MI was attenuated in antagomiR‐146 treated mice by increasing the expression of TIMP4, which indicated that the inhibition of miR‐146b‐5p might become an effective therapeutic approach for preventing atrial fibrosis.
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