Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents
Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents
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DOI：
10.1172/jci40973
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发表时间：
2010-07-01
影响因子：
15.9
通讯作者：
Fukuda, Keiichi
中科院分区：
文献类型：
--
作者：
Hakuno, Daihiko;Kimura, Naritaka;Fukuda, Keiichi
瓣膜性心脏病（VHD）是指涉及一个或多个心脏瓣膜的任何疾病过程。这种情况可以是先天性的，也可以是后天性的，例如动脉粥样硬化或风湿热。尽管它的临床重要性，分子机制的基础VHD仍然未知。我们研究了骨膜蛋白在退行性VHD中的病理生理作用和分子机制，骨膜蛋白是一种在心脏瓣膜发育中起关键作用的蛋白质。出乎意料的是，我们发现在人动脉粥样硬化和风湿性VHD的血管生成区域中，在浸润的炎性细胞和肌成纤维细胞中，骨膜蛋白水平急剧增加，而在正常瓣膜中，骨膜蛋白定位于内皮下层。骨膜蛋白和软骨调节素I（一种维持心脏瓣膜功能的血管抑制因子）的表达模式相互排斥。在WT小鼠中，高脂饮食显著增加主动脉瓣增厚，环状纤维化，MMP-2和MMP-13表达水平，伴随着骨膜蛋白表达增加;这些变化在骨膜蛋白敲除小鼠中减弱。在体外和离体研究表明，骨膜蛋白促进管的形成和动员的EC。此外，骨膜蛋白显着增加MMP分泌从培养的瓣膜间质细胞，内皮细胞和巨噬细胞在细胞类型特异性的方式。这些发现表明，与软骨调节蛋白I相反，骨膜蛋白通过诱导血管生成和MMP产生在心脏瓣膜复合体变性的进展中起重要作用。
Valvular heart disease (VHD) is the term given to any disease process involving one or more of the heart valves. The condition can be congenital or acquired, for example as a result of atherosclerosis or rheumatic fever. Despite its clinical importance, the molecular mechanisms underlying VHD remain unknown. We investigated the pathophysiologic role and molecular mechanism of periostin, a protein that plays critical roles in cardiac valve development, in degenerative VHD. Unexpectedly, we found that periostin levels were drastically increased in infiltrated inflammatory cells and myofibroblasts in areas of angiogenesis in human atherosclerotic and rheumatic VHD, whereas periostin was localized to the subendothelial layer in normal valves. The expression patterns of periostin and chondromodulin I, an angioinhibitory factor that maintains cardiac valvular function, were mutually exclusive. In WT mice, a high-fat diet markedly increased aortic valve thickening, annular fibrosis, and MMP-2 and MMP-13 expression levels, concomitant with increased periostin expression; these changes were attenuated in periostin-knockout mice. In vitro and ex vivo studies revealed that periostin promoted tube formation and mobilization of ECs. Furthermore, periostin prominently increased MMP secretion from cultured valvular interstitial cells, ECs, and macrophages in a cell type-specific manner. These findings indicate that, in contrast to chondromodulin I, periostin plays an essential role in the progression of cardiac valve complex degeneration by inducing angiogenesis and MMP production.