Exosomes mediated fibrogenesis in dilated cardiomyopathy through a MicroRNA pathway.
Exosomes mediated fibrogenesis in dilated cardiomyopathy through a MicroRNA pathway.
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DOI：
10.1016/j.isci.2023.105963
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发表时间：
2023-02-17
期刊：
影响因子：
5.8
通讯作者：
Kaushal, Sunjay
中科院分区：
文献类型：
--
作者：
Fu, Xuebin;Mishra, Rachana;Chen, Ling;Arfat, Mir Yasir;Sharma, Sudhish;Kingsbury, Tami;Gunasekaran, Muthukumar;Saha, Progyaparamita;Hong, Charles;Yang, Peixin;Li, Deqiang;Kaushal, Sunjay
心脏纤维化是晚期家族性扩张型心肌病（DCM）患者的一个标志，尽管其潜在机制仍不清楚。心脏外泌体（Exos）与缺血性心肌病纤维化有关。因此，我们研究了家族性DCM心肌细胞分泌的Exos是否可以促进纤维化。使用人iPSC分化的心肌细胞，我们从DCM或对照（CTL）心肌细胞分离血管紧张素II刺激条件培养基的Exos。令人感兴趣的是，培养的心脏成纤维细胞在暴露于DCM-Exos而不是CTL-Exos后具有增加的纤维形成。同时，将DCM-Exos注射到小鼠心脏中增强了心脏纤维化和心功能受损。从机制上讲，我们确定了DCM-Exos中miRNA-218- 5 p的上调是纤维发生的关键因素。miRNA-218- 5 p通过抑制TNFAIP 3（一种主要炎症抑制剂）激活TGF-β信号传导。总之，我们的结果说明了心肌细胞来源的Exos的促纤维化作用，这突出了DCM中心脏纤维化的另一个发病机制途径。血管紧张素II调节的DCM心肌细胞分泌外泌体以促进纤维化DCM外泌体中miR-218- 5 p的高度存在介导促纤维化作用TNFAIP 3在miR-218- 5 p诱导的TGF-β活化中起重要作用纤维化;细胞生物学
Cardiac fibrosis is a hallmark in late-stage familial dilated cardiomyopathy (DCM) patients, although the underlying mechanism remains elusive. Cardiac exosomes (Exos) have been reported relating to fibrosis in ischemic cardiomyopathy. Thus, we investigated whether Exos secreted from the familial DCM cardiomyocytes could promote fibrogenesis. Using human iPSCs differentiated cardiomyocytes we isolated Exos of angiotensin II stimulation conditioned media from either DCM or control (CTL) cardiomyocytes. Of interest, cultured cardiac fibroblasts had increased fibrogenesis following exposure to DCM-Exos rather than CTL-Exos. Meanwhile, injecting DCM-Exos into mouse hearts enhanced cardiac fibrosis and impaired cardiac function. Mechanistically, we identified the upregulation of miRNA-218-5p in the DCM-Exos as a critical contributor to fibrogenesis. MiRNA-218-5p activated TGF-β signaling via suppression of TNFAIP3, a master inflammation inhibitor. In conclusion, our results illustrate a profibrotic effect of cardiomyocytes-derived Exos that highlights an additional pathogenesis pathway for cardiac fibrosis in DCM. Angiotensin II conditioned DCM cardiomyocytes secrete exosomes to promote fibrosis Highly present of miR-218-5p in DCM exosomes mediate the profibrotic effect TNFAIP3 plays an essential role in the miR-218-5p induced TGF-beta activation Fibrosis; Cell biology
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