Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease.
Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease.
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DOI：
10.1016/j.yjmcc.2013.04.001
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发表时间：
2013-07
影响因子：
5
通讯作者：
Garg V
中科院分区：
文献类型：
--
作者：
Bosse K;Hans CP;Zhao N;Koenig SN;Huang N;Guggilam A;LaHaye S;Tao G;Lucchesi PA;Lincoln J;Lilly B;Garg V
成熟的主动脉瓣由结构良好的三层细胞外基质组成，其间夹杂着主动脉瓣间质细胞(AVICs)，并被内皮覆盖。瓣膜内皮功能障碍引发邻近动静脉动静脉内膜细胞钙化，导致钙化性主动脉瓣病(CAVD)。血管内皮细胞与血管内皮细胞通讯并导致疾病的分子机制尚不清楚。通过共培养实验，我们发现内皮细胞可以分泌抑制血管内皮细胞钙化的信号。一氧化氮(NO)的获得或丢失分别阻止或加速了AVICs的钙化，提示内皮细胞来源的信号是NO。在基因上与人类CAVD有关的Notch1的过表达，可以延缓没有抑制作用的AVICs的钙化。在AVICs中，NO调节Notch1下游靶点Hey1的表达，并改变Notch1胞内区的核定位。最后，Notch1和NOS3(内皮型一氧化氮合酶)显示了体内的遗传相互作用，对瓣膜的正常形态形成和主动脉瓣疾病的发展至关重要。我们的数据表明，内皮细胞来源的NO是AVICs中Notch1信号的调节因子，参与了主动脉瓣和成人主动脉瓣疾病的发生发展。
The mature aortic valve is composed of a structured trilaminar extracellular matrix that is interspersed with aortic valve interstitial cells (AVICs) and covered by endothelium. Dysfunction of the valvular endothelium initiates calcification of neighboring AVICs leading to calcific aortic valve disease (CAVD). The molecular mechanism by which endothelial cells communicate with AVICs and cause disease is not well understood. Using a co-culture assay, we show that endothelial cells secrete a signal to inhibit calcification of AVICs. Gain or loss of nitric oxide (NO) prevents or accelerates calcification of AVICs, respectively, suggesting that the endothelial cell-derived signal is NO. Overexpression of Notch1, which is genetically linked to human CAVD, retards the calcification of AVICs that occurs with NO inhibition. In AVICs, NO regulates the expression of Hey1, a downstream target of Notch1, and alters nuclear localization of Notch1 intracellular domain. Finally, Notch1 and NOS3 (endothelial NO synthase) display an in vivo genetic interaction critical for proper valve morphogenesis and the development of aortic valve disease. Our data suggests that endothelial cell-derived NO is a regulator of Notch1 signaling in AVICs in the development of the aortic valve and adult aortic valve disease.
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影响因子：
5.7
作者：
Rajamannan, NM;Subramaniam, M;Spelsberg, TC
通讯作者：
Spelsberg, TC
影响因子：
24
作者：
Miller, Jordan D.;Chu, Yi;Brooks, Robert M.;Richenbacher, Wayne E.;Pena-Silva, Ricardo;Heistad, Donald D.
通讯作者：
Heistad, Donald D.
DOI：
10.1161/atvbaha.111.227561
发表时间：
2011-07-01
影响因子：
8.7
作者：
Nus, Meritxell;MacGrogan, Donal;Luis de la Pompa, Jose
通讯作者：
Luis de la Pompa, Jose
影响因子：
--
作者：
Gridley, Thomas
通讯作者：
Gridley, Thomas
影响因子：
64.8
作者：
Garg, V;Muth, AN;Srivastava, D
通讯作者：
Srivastava, D