The mir-200 family regulates key pathogenic events in ascending aortas of individuals with bicuspid aortic valves.
The mir-200 family regulates key pathogenic events in ascending aortas of individuals with bicuspid aortic valves.
复制标题
miR-200家族调节双质主动脉瓣升主动脉的关键致病事件。
DOI：
10.1111/joim.12833
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发表时间：
2019-01
影响因子：
11.1
通讯作者：
Eriksson P
中科院分区：
文献类型：
--
作者：
Maleki S;Cottrill KA;Poujade FA;Bhattachariya A;Bergman O;Gådin JR;Simon N;Lundströmer K;Franco-Cereceda A;Björck HM;Chan SY;Eriksson P
与具有三尖瓣主动脉瓣（TAV）的正常人群相比，具有二叶式主动脉瓣（BAV）的个体在升主动脉中发生动脉瘤的风险显著更高。已知BAV和TAV患者的动脉瘤形成在分子水平上是不同的，但其潜在机制尚不明确。在这里，我们研究了与TAV相比，微小RNA（miRNA）（基因表达的重要转录后调节因子）在BAV患者的主动脉疾病中的作用，但尚未完全描述。使用系统生物学方法，基于从BAV和TAV患者的非扩张性动脉瘤的蛋白质组学分析中获得的数据，我们构建了与观察到的差异蛋白质特征相关的调控microRNA的基因相互作用网络。miR-200家族是排名最高的miRNA，因此可能对BAV相关信号网络具有最强的影响。此外，qRT-PCR和ChIP分析显示BAV患者中miR-200 c的表达较低，miR-200靶基因、ZEB 1/ZEB 2转录因子的表达较高，miR-200 c启动子被ZEB 1/ZEB 2的染色质占据较高，表明miR-200 c/ZEBs负反馈环和内皮/上皮间质转化（EndMT/EMT）的诱导。我们认为，EndMT/EMT的miR-200依赖性过程是一种合理的生物学机制，使BAV升主动脉更容易发生动脉瘤。虽然最初由miR-200 c/ZEB反馈环支持，但这一过程最有可能是通过其他miRNA的合作来推进的。
An individual with a bicuspid aortic valve (BAV) runs a substantially higher risk of developing aneurysm in the ascending aorta compared to the normal population with tricuspid aortic valves (TAV). Aneurysm formation in patients with BAV and TAV is known to be distinct at the molecular level but the underlying mechanisms are undefined. Here, we investigated the still incompletely described role of microRNAs (miRNAs), important post‐transcriptional regulators of gene expression, in such aortic disease of patients with BAV as compared with TAV. Using a system biology approach, based on data obtained from proteomic analysis of non‐dilated aortas from BAV and TAV patients, we constructed a gene‐interaction network of regulatory microRNAs associated with the observed differential protein signature. The miR‐200 family was the highest ranked miRNA, hence potentially having the strongest effect on the signalling network associated with BAV. Further, qRT‐PCR and ChIP analyses showed lower expression of miR‐200c, higher expression of miR‐200 target genes, ZEB1/ZEB2 transcription factors, and higher chromatin occupancy of the miR‐200c promoter by ZEB1/ZEB2 in BAV patients, indicating a miR‐200c/ZEBs negative feedback loop and induction of endothelial/epithelial mesenchymal transition (EndMT/EMT). We propose that a miR‐200‐dependent process of EndMT/EMT is a plausible biological mechanism rendering the BAV ascending aorta more prone to aneurysm development. Although initially supported by a miR‐200c/ZEB feedback loop, this process is most probably advanced by cooperation of other miRNAs.
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影响因子：
3.7
作者：
Katz B;Reis ST;Viana NI;Morais DR;Moura CM;Dip N;Silva IA;Iscaife A;Srougi M;Leite KR
通讯作者：
Leite KR
影响因子：
4.8
作者：
Eades, Gabriel;Yao, Yuan;Zhou, Qun
通讯作者：
Zhou, Qun
影响因子：
--
作者：
Follo, Matilde Y;Manzoli, Lucia;Cocco, Lucio
通讯作者：
Cocco, Lucio
影响因子：
3.9
作者：
Cai, Zhi-Gang;Zhang, Shao-Ming;Xu, Xiao-Ping
通讯作者：
Xu, Xiao-Ping
影响因子：
20.1
作者：
Lagendijk, Anne Karine;Goumans, Marie Jose;Bakkers, Jeroen
通讯作者：
Bakkers, Jeroen