Altered versican cleavage in ADAMTS5 deficient mice; a novel etiology of myxomatous valve disease.
Altered versican cleavage in ADAMTS5 deficient mice; a novel etiology of myxomatous valve disease.
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DOI：
10.1016/j.ydbio.2011.06.041
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发表时间：
2011-09-01
影响因子：
2.7
通讯作者：
Kern CB
中科院分区：
文献类型：
--
作者：
Dupuis LE;McCulloch DR;McGarity JD;Bahan A;Wessels A;Weber D;Diminich AM;Nelson CM;Apte SS;Kern CB
在胎儿瓣膜成熟中，内膜垫的相对均一的富含蛋白聚糖的细胞外基质（ECM）被成熟瓣膜中发现的专门和分层的ECM取代的机制尚不清楚。因此，我们推断，揭示蛋白酶的关键'重塑'富含蛋白聚糖（细胞外基质）ECM可能阐明新的机制，瓣膜的发展。我们已经确定，ADAMTS 5（一种具有血栓蛋白1型基序的去整合素样和金属蛋白酶结构域）缺陷的小鼠表现出瓣膜增大，我们证明ADAMTS 5在心脏瓣膜成熟期间主要由瓣膜内皮细胞表达。ADAMTS 5缺陷型瓣膜的底物多功能蛋白聚糖（一种关键的心脏蛋白聚糖）的切割减少。在Adamts 5 −/−小鼠中，通过Vcan杂合性实现的多功能蛋白聚糖的体内减少，基本上挽救了瓣膜异常。在Adamts 5 −/−瓣膜间充质中观察到BMP 2免疫定位、Sox 9表达和间充质细胞增殖的增加，并与Adamts 5 −/−瓣膜尖中海绵体（富含蛋白聚糖）区域的扩张相关。此外，这些数据表明，ECM重塑通过ADAMTS 5所需的内皮细胞间质信号在晚期胎儿瓣膜发育。虽然成年Adamts 5 −/−小鼠是可行的，但它们不能从发育的瓣膜异常中恢复，并且具有100%变性的粘液瘤性心脏瓣膜。由于蛋白多糖的积累是粘液瘤性瓣膜病的标志，基于这些数据，我们假设胎儿瓣膜发育过程中多功能蛋白聚糖裂解的缺乏可能是成人粘液瘤性瓣膜病的潜在病因。
In fetal valve maturation the mechanisms by which the relatively homogeneous proteoglycan-rich extracellular matrix (ECM) of endocardial cushions is replaced by a specialized and stratified ECM found in mature valves are not understood. Therefore, we reasoned that uncovering proteases critical for ‘remodeling’ the proteoglycan rich (extracellular matrix) ECM may elucidate novel mechanisms of valve development. We have determined that mice deficient in ADAMTS5, (A Disintegrin-like And Metalloprotease domain with ThromboSpondin-type 1 motifs) which we demonstrated is expressed predominantly by valvular endocardium during cardiac valve maturation, exhibited enlarged valves. ADAMTS5 deficient valves contained a reduction in cleavage of its substrate versican, a critical cardiac proteoglycan. In vivo reduction of versican, in Adamts5−/− mice, achieved through Vcan heterozygosity, substantially rescued the valve anomalies. An increase in BMP2 immunolocalization, Sox9 expression and mesenchymal cell proliferation were observed in Adamts5−/− valve mesenchyme and correlated with expansion of the spongiosa (proteoglycan-rich) region in Adamts5−/− valve cusps. Furthermore, these data suggest that ECM remodeling via ADAMTS5 is required for endocardium to mesenchymal signaling in late fetal valve development. Although adult Adamts5−/− mice are viable they do not recover from developmental valve anomalies and have myxomatous cardiac valves with 100% penetrance. Since the accumulation of proteoglycans is a hallmark of myxomatous valve disease, based on these data we hypothesize that a lack of versican cleavage during fetal valve development may be a potential etiology of adult myxomatous valve disease.
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影响因子：
37.8
作者：
Aikawa, E;Whittaker, P;Schoen, FJ
通讯作者：
Schoen, FJ
影响因子：
20.1
作者：
Henderson, DJ;Copp, AJ
通讯作者：
Copp, AJ
影响因子：
10.5
作者：
Akiyama, H;Chaboissier, MC;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
4.6
作者：
Délot, EC;Bahamonde, ME;Lyons, KM
通讯作者：
Lyons, KM
DOI：
10.1073/pnas.94.19.10116
发表时间：
1997-09-16
影响因子：
11.1
作者：
Aspberg, A;Miura, R;Yamaguchi, Y
通讯作者：
Yamaguchi, Y