Chondromodulin-I maintains cardiac valvular function by preventing angiogenesis
Chondromodulin-I maintains cardiac valvular function by preventing angiogenesis
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DOI：
10.1038/nm1476
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发表时间：
2006-10-01
期刊：
影响因子：
82.9
通讯作者：
Fukuda, Keiichi
中科院分区：
文献类型：
--
作者：
Yoshioka, Masatoyo;Yuasa, Shinsuke;Fukuda, Keiichi
心脏瓣膜的无血供在几种瓣膜性心脏病（VHD）中被废除。本研究探讨了瓣膜无血运的分子机制及其与VHD的相关性。软骨调节素-l是一种从软骨中分离的抗血管生成因子，在心脏瓣膜中大量表达。软骨调节素-1的基因靶向导致老年小鼠心脏瓣膜中增强的Vegf-A表达、血管生成、脂质沉积和钙化。超声心动图显示主动脉瓣增厚、钙化和湍流，提示主动脉瓣狭窄的早期变化。从培养的瓣膜间质细胞获得的条件培养基强烈抑制管的形成和动员的内皮细胞，并诱导其凋亡，这些影响被部分抑制软骨调节素-l小干扰RNA。在人VHD中，包括与感染性心内膜炎、风湿性心脏病和动脉粥样硬化相关的病例，在软骨调节素-l下调的区域观察到VEGF-A表达、新生血管形成和钙化。这些发现提供了证据表明，软骨调节素-l在通过防止可能导致VHD的血管生成来维持瓣膜正常功能方面具有关键作用。
The avascularity of cardiac valves is abrogated in several valvular heart diseases (VHDs). This study investigated the molecular mechanisms underlying valvular avascularity and its correlation with VHD. Chondromodulin-l, an antiangiogenic factor isolated from cartilage, is abundantly expressed in cardiac valves. Gene targeting of chondromodulin-l resulted in enhanced Vegf-A expression, angiogenesis, lipid deposition and calcification in the cardiac valves of aged mice. Echocardiography showed aortic valve thickening, calcification and turbulent flow, indicative of early changes in aortic stenosis. Conditioned medium obtained from cultured valvular interstitial cells strongly inhibited tube formation and mobilization of endothelial cells and induced their apoptosis; these effects were partially inhibited by chondromodulin-l small interfering RNA. In human VHD, including cases associated with infective endocarditis, rheumatic heart disease and atherosclerosis, VEGF-A expression, neovascularization and calcification were observed in areas of chondromodulin-l downregulation. These findings provide evidence that chondromodulin-l has a pivotal role in maintaining valvular normal function by preventing angiogenesis that may lead to VHD.