Human myxomatous mitral valve prolapse role of bone morphogenetic protein 4 in valvular interstitial

AbstractGo to:Myxomatous Mitral Valve Prolapse (MVP) is the most common indication for mitral valve surgery due to severe mitral regurgitation. Echocardiographically, MVP is defined as a single or bileaflet prolapse, at least 2 mm beyond the long-axis annular plane, with or without leaflet thickening (Freed et al., 1999). The prevalence of MVP is estimated at 2–3%, and is equally distributed between men and women. MVP is expected to occur in approximately 7.2 million individuals in the US, and over 144 million worldwide (Freed et al., 1999, 2001).粘液瘤二尖瓣脱垂（MVP）是最常见的适应症二尖瓣手术由于严重的二尖瓣关闭不全。

超声心动图，MVP被定义为单个或双叶脱垂，至少2mm超出长轴环状平面，有或没有叶增厚（弗里德等人，1999）。

MVP的患病率估计为2-3％，而男女之间平均分配。

MVP有望出现在美国大约720万的个人和超过1.44亿全球（弗里德等人，1999年，2001年）。

The process of Heart valve development is conserved along vertebrate species. The valve leaflets originate from mesenchymal outgrowths known as endocardial cushions, the precursors of valves and the cardiac septa. A subgroup of cells in thecushion-forming area, driven by signals from the underlying myocardium, undergoes endothelial to mesenchymal cell transition (EMT) and migrate into the cardiac jelly to form Valvular Interstitial Cells (VICs) (Schoen, 2008). VICs, from all four heart valves, share the same embryologic origin and maintain similar mesenchymal features once differentiated in adult cells. Although adult valves are sparsely populated with quiescent VICs, dynamic changes in ECM architecture and VIC phenotypes continue in response to altered mechanical and/or pathological conditions (Schoen, 2008; Coombs and Yutzey, 2009; Garg, 2006; Hinton and Yutzey, 2011). This concept has been investigated for aortic valve pathologies, however, little is known about the cellular plasticity of VICs during the pathogenesis of mitral valve diseases (Chen et al., 2009). Here, we investigated the role of VIC activation in human myxomatous MVP-derived tissues, and analyzed the direct effects of these phenotypic changes on ECM reorganization by testing MVP- and control-derived VICs plasticity.心脏瓣膜发展的过程中被沿脊椎动物物种保守的。

瓣叶从被称为心内膜垫，阀的前体和心脏隔膜间质副产物起源。

细胞在垫形成区域中，通过信号从底层心肌从动的一个分组，经过内皮间质细胞转化（EMT），并迁移到心脏果冻以形成瓣膜质细胞（的VIC）（舒恩，2008）。

的VIC，从所有四个心脏瓣膜，共享相同的胚胎起源和维持一次分化成人细胞间质相似的特征。

虽然成人阀人口稀少与静态的VIC，在ECM架构和VIC 表型的动态变化响应于改变的机械和/或病理学病症（;库姆斯和Yutzey，2009; Garg 则2006;欣顿和Yutzey2011舒恩，2008）继续。

此概念已被研究用于主动脉瓣膜病症，然而，很少有人的二尖瓣疾病的发病机制中已知的VIC有关的细胞可塑性（Chen 等，2009）。

这里，我们调查VIC活化中的作用在人粘液MVP衍生组织中，并通过测试MVP-和控制衍生的VIC可塑性分析对ECM重组这些表型变化的直接影响。

VICs are the most abundant cell types in the mitral valves and are distributed throughout all its layers: a dense collagenous layer close to the outflow surface which provides the primary strength component (Fibrosa); a central core of loose connective tissue (Spongiosa); and a layer rich in elastin below the inflow surface (Atrialis) (Prunotto et al., 2010; Rabkin et al., 2001). The key microscopic changes in MVP appear to occur in the spongiosa and fibrosa, where the structural integrity of the entire valve resides. Alterations in matrix components (collagen, elastin, proteoglycans and matrix metalloproteinase and their tissue inhibitors) and ECM reorganization have been studied extensively, however very little is known about the cellular elements and molecular mechanisms leading to mitral VIC activation (Rabkin et al., 2004; Taylor et al., 2003).的VIC是在二尖瓣中最丰富的细胞类型，并分布在其整个所有层：致密胶原层靠近流出表面，它提供的主强度部件（炎）;疏松结缔组织的中央芯（松质）;和一层富含弹性蛋白的流入面（Atrialis）以下（Prunotto等人，2010;拉布金等人，2001年）。

在MVP中的关键微观变化似乎发生在松质和炎，其中整个阀的结构完整性驻留。

在基质成分（胶原，弹性蛋白，蛋白多糖和基质金属蛋白酶和它们的组织抑制剂）和ECM重组改变已被广泛研究，但很少有人知道蜂窝元素和导致二尖瓣VIC 激活（分子机制拉布金等人，2004年;泰勒等人，2003）。

Recent studies have suggested developmentally regulated expression of Bone Morphogenetic Proteins (BMPs) and Sox9 during the atrioventricular valve formation (Jiao et al., 2003). BMPs belong to TGF-β super family of cytokines, and have been implicated in numerous developmental processes including proper septation and valvulogenesis. BMP-2 and BMP-4 are known to be potent osteogenic morphogens and are shown to be present in ossified valves (Mohler et al., 2001). BMP4 is also a potent inducer of collagen, proteoglycan synthesis and matrix mineralization. It acts as a signal from the myocardium directly mediating atrioventricular septation, and defects in this process are shown to cause one of the most common human congenital heart abnormalities, atrioventricular canal defect (Jiao et al., 2003). A possible association of BMP signaling pathways is suggested in a MMP-2 transgenic mouse model of MVP (Mahimkar et al., 2009). The present study was carried out on the most common presentation of myxomatous mitral valve disease, posterior leaflet prolapse of the anatomic area described in the Carpentier‟s classification as P2 or middle scallop of the posterior leaflet (Carpentier et al., 1980). Based on our tissue microarray analysis andMV-derived cell analysis we hypothesized that BMP4 mediates the activation of VICs from healthy quiescent cells to the pathologic synthetic phenotype during developmentof MVP. This study, for the first time, describes a molecular mechanism leading to the activation of quiescent VICs and its effect on ECM remodeling in human myxomatous Mitral Valve Prolapse.最近的研究表明骨形态发生蛋白（BMPs）和Sox9的的发育调节表达在房室瓣形成（焦等人，2003）。