Notch1 represses osteogenic pathways in aortic valve cells.
Notch1 represses osteogenic pathways in aortic valve cells.
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DOI：
10.1016/j.yjmcc.2009.08.008
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发表时间：
2009-12
影响因子：
5
通讯作者：
Srivastava, Deepak
中科院分区：
文献类型：
--
作者：
Nigam, Vishal;Srivastava, Deepak
钙化性主动脉瓣狭窄是成人心脏病的第三大原因，也是发达国家获得性瓣膜病的最常见形式。然而，导致钙化的分子途径知之甚少。我们报告了两个家系，其中NOTCH 1杂合突变导致二叶式主动脉瓣和严重的主动脉瓣钙化。NOTCH 1是参与细胞命运决定、细胞分化和心脏瓣膜形成的高度保守的信号通路的一部分。在这项研究中，我们研究了NOTCH 1抑制主动脉瓣钙化的机制。杂合子Notch 1-null（Notch 1 +/−）小鼠的主动脉瓣钙化是年龄和性别匹配的野生型同窝小鼠的五倍以上。在培养的绵羊主动脉瓣间质细胞（AVIC）中抑制Notch信号传导也使钙化增加了五倍以上，并导致成骨细胞典型的基因表达。我们发现，Notch 1通常抑制基因编码的骨形态发生蛋白2（BMP 2）在小鼠主动脉瓣在体内和主动脉瓣细胞在体外。siRNA介导的Bmp 2敲低阻断了AVIC中Notch抑制诱导的钙化。这些发现表明，Notch 1信号在主动脉瓣细胞抑制成骨细胞样钙化途径介导的Bmp 2。
Calcific aortic stenosis is the third leading cause of adult heart disease and the most common form of acquired valvular disease in developed countries. However, the molecular pathways leading to calcification are poorly understood. We reported two families in which heterozygous mutations in NOTCH1 caused bicuspid aortic valve and severe aortic valve calcification. NOTCH1 is part of a highly conserved signaling pathway involved in cell fate decisions, cell differentiation, and cardiac valve formation. In this study, we examined the mechanism by which NOTCH1represses aortic valve calcification. Heterozygous Notch1-null (Notch1+/−) mice had greater than fivefold more aortic valve calcification than age- and sex-matched wildtype littermates. Inhibition of Notch signaling in cultured sheep aortic valve interstitial cells (AVICs) also increased calcification more than fivefold and resulted in gene expression typical of osteoblasts. We found that Notch1 normally represses the gene encoding bone morphogenic protein 2 (Bmp2) in murine aortic valves in vivo and in aortic valve cells in vitro. siRNA-mediated knockdown of Bmp2 blocked the calcification induced by Notch inhibition in AVICs. These findings suggest that Notch1 signaling in aortic valve cells represses osteoblast-like calcification pathways mediated by Bmp2.
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影响因子：
46.9
作者：
Chen, Vincent C.;Stull, Robert;Joo, Daniel;Cheng, Xin;Keller, Gordon
通讯作者：
Keller, Gordon
影响因子：
2.7
作者：
Nakagawa, O;Nakagawa, M;Srivastava, D
通讯作者：
Srivastava, D
影响因子：
4.6
作者：
Jian, B;Narula, N;Levy, RJ
通讯作者：
Levy, RJ
影响因子：
5.8
作者：
Caprera, Andrea;Lazzari, Barbara;Mariani, Paola
通讯作者：
Mariani, Paola
DOI：
10.1016/j.jtcvs.2007.02.041
发表时间：
2007-08-01
影响因子：
6
作者：
McKellar, Stephen H.;Tester, David J.;Sundt, Thoralf M., III
通讯作者：
Sundt, Thoralf M., III