Conserved transcriptional regulatory mechanisms in aortic valve development and disease.
Conserved transcriptional regulatory mechanisms in aortic valve development and disease.
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DOI：
10.1161/atvbaha.113.302071
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Yutzey KE
中科院分区：
文献类型：
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作者：
Wirrig EE;Yutzey KE
有越来越多的证据表明，在心脏瓣膜疾病的发育转录调控途径的激活。在这里，我们审查分子调控机制参与心脏瓣膜祖细胞的发展，小叶形态发生，细胞外基质组织，也积极在患病的主动脉瓣。这些包括内皮细胞向间充质细胞转化的调节因子，如Notch途径效应子RBPJ，以及瓣膜祖细胞标志物Twist 1、Msx 1/2和Sox 9。在成人主动脉瓣中，这些发育机制的潜在修复或病理功能知之甚少，但推测瓣膜祖细胞可能有助于疾病背景下的修复是诱人的。同样，RBPJ或Sox 9的缺失导致小鼠主动脉瓣钙化，支持在预防疾病中的潜在治疗作用。在主动脉瓣钙化过程中，除了瓣膜祖细胞调控程序外，成骨发育的转录调控因子也被激活。具体而言，转录因子Runx 2及其下游靶基因在钙化瓣膜中被诱导。Runx 2和成骨基因也会被血管钙化诱导，但瓣膜祖细胞标志物的激活和表达的细胞背景可能因瓣膜和血管钙化而不同。有必要进行更多的研究，以确定发育机制是否有助于瓣膜修复，或者这些途径是否可以用于心脏瓣膜疾病的新治疗。
There is increasing evidence for activation of developmental transcriptional regulatory pathways in heart valve disease. Here we review molecular regulatory mechanisms involved in heart valve progenitor development, leaflet morphogenesis, and extracellular matrix organization that also are active in diseased aortic valves. These include regulators of endothelial-to-mesenchymal transitions, such as the Notch pathway effector RBPJ, and the valve progenitor markers Twist1, Msx1/2, and Sox9. Little is known of the potential reparative or pathological functions of these developmental mechanisms in adult aortic valves, but it is tempting to speculate that valve progenitor cells could contribute to repair in the context of disease. Likewise, loss of either RBPJ or Sox9 leads to aortic valve calcification in mice, supporting a potential therapeutic role in prevention of disease. During aortic valve calcification, transcriptional regulators of osteogenic development are activated in addition to valve progenitor regulatory programs. Specifically, the transcription factor Runx2 and its downstream target genes are induced in calcified valves. Runx2 and osteogenic genes also are induced with vascular calcification, but activation of valve progenitor markers and the cellular context of expression are likely to be different for valve and vascular calcification. Additional research is necessary to determine if developmental mechanisms contribute to valve repair or if these pathways can be harnessed for new treatments of heart valve disease.