Bone Marrow-Derived MicroRNA-223 Works as an Endocrine Genetic Signal in Vascular Endothelial Cells and Participates in Vascular Injury From Kawasaki Disease.
Bone Marrow-Derived MicroRNA-223 Works as an Endocrine Genetic Signal in Vascular Endothelial Cells and Participates in Vascular Injury From Kawasaki Disease.
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DOI：
10.1161/jaha.116.004878
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发表时间：
2017-02-14
影响因子：
5.4
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Chu M;Wu R;Qin S;Hua W;Shan Z;Rong X;Zeng J;Hong L;Sun Y;Liu Y;Li W;Wang S;Zhang C
川崎病(KD)是儿童获得性心脏病最常见的病因，其原因不明，导致永久性冠状动脉损伤。本研究试图确定血中microRNA miR-223在KD和KD诱导的血管内皮细胞(ECs)损伤中的作用及其机制。用基因芯片分析KD患者和健康对照血清中的microRNA图谱。我们注意到多个血清microRNAs在KD中异常表达，其中miR-223是上调最丰富的血清microRNA。我们发现骨髓来源的血细胞(白细胞和血小板)能够向血清中分泌miR-223。血管内皮细胞无内源性miR-223，但血细胞分泌的血清miR-223可进入血管壁的血管内皮细胞。外源miR-223通过其靶基因IGF1R对EC功能具有很强的生物学效应。有趣的是，KD诱导的EC损伤与miR-223的增加有关，因为它们被miR-223基因敲除所抑制。最后，使用miR-223基因敲除小鼠和通过将miR-223基因敲除小鼠的骨髓移植到野生型小鼠而产生的嵌合小鼠来验证这些观察结果。KD患者内皮细胞中血细胞源性miR-223水平显著升高。内皮细胞中miR-223的增加可能作为一种新的内分泌遗传信号参与KD的血管损伤。MIR-223可能为KD血管并发症的治疗提供新的机制和新的治疗靶点。
Kawasaki disease (KD) is now the most common cause of acquired cardiac disease in children due to permanent coronary artery damage with unknown etiology. The study sought to determine the role of blood microRNA miR‐223 in KD and KD‐induced injuries in vascular endothelial cells (ECs) as well as the mechanisms involved. MicroRNA profiles in serum from patients with KD and from healthy controls were assessed by microarray analysis. We noted that multiple serum microRNAs were aberrantly expressed in KD, among them miR‐223, which was the most upregulated abundant serum microRNA. We found that bone marrow–derived blood cells (leukocytes and platelets) were able to secrete miR‐223 into serum. Vascular ECs had no endogenous miR‐223; however, the blood cell–secreted serum miR‐223 could enter into the vascular ECs in the vascular walls. The exogenous miR‐223 had strong biological effects on EC functions via its target genes such as IGF1R. Interestingly, KD‐induced EC injuries were related to increased miR‐223 because they were inhibited by miR‐223 knockdown. Finally, these observations were verified using miR‐223 knockout mice and the chimeric mice generated by transplantation of bone marrow from miR‐223 knockout mice into wild‐type mice. In KD patients, the levels of blood cell–derived miR‐223 in ECs are significantly increased. The increased miR‐223 in ECs could work as a novel endocrine genetic signal and participate in vascular injury of KD. MiR‐223 may provide a novel mechanism and a new therapeutic target for vascular complication of KD.