Fibroblast protein profile analysis highlights the role of oxidative stress and vitamin K recycling in the pathogenesis of pseudoxanthoma elasticum
Fibroblast protein profile analysis highlights the role of oxidative stress and vitamin K recycling in the pathogenesis of pseudoxanthoma elasticum
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DOI：
10.1002/prca.200900007
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发表时间：
2009-09-01
影响因子：
2
通讯作者：
Quaglino, Daniela
中科院分区：
文献类型：
--
作者：
Boraldi, Federica;Annovi, Giulia;Quaglino, Daniela
弹性假黄瘤是一种与ABCC6基因突变相关的遗传性疾病，然而，导致弹性纤维钙化和临床表现的发病机制尚不清楚。真皮成纤维细胞直接参与细胞外环境的产生，已从健康受试者和受PXE影响的患者中分离出来，在体外培养，并对其产生活性氧的能力、细胞膜的结构和功能特性以及蛋白质组分的变化进行了表征。数据表明，氧化应激对PXE成纤维细胞表型具有深远和持久的影响，其原因包括：全球DNA甲基化水平降低，碳化蛋白质和脂质过氧化产物数量增加，细胞膜结构属性改变，蛋白质表达改变。数据揭示了PXE的发病途径，确定了通过低效率的维生素K循环影响弹性纤维钙化的蛋白质网络，并强调了差异表达蛋白质作为靶点的作用，以验证未来旨在延缓和/或逆转PXE成纤维细胞病理表型的治疗策略的有效性。此外，数据为在没有ABCC6突变的情况下研究PXE样表型开辟了新的视角。
Pseudoxanthoma elasticum (PXE) is a genetic disorder associated to mutations in the ABCC6 gene; however, the pathogenetic mechanisms leading to elastic fibre calcifications and to clinical manifestations are still unknown. Dermal fibroblasts, directly involved in the production of the extracellular milieu, have been isolated from healthy subjects and from patients affected by PXE, cultured in vitro and characterized for their ability to produce reactive oxygen species, for structural and functional properties of their cell membranes, for changes in their protein profile. Data demonstrate that oxidative stress has profound and endurable consequences on PXE fibroblast phenotype being responsible for: reduced levels of global DNA methylation, increased amount of carbonylated proteins and of lipid peroxidation products, altered structural properties of cell membranes, modified protein expression. Data shed new light on the pathogenetic pathways in PXE, by identifying a network of proteins affecting elastic fibre calcification through inefficient vitamin K recycling, and highlight the role of differentially expressed proteins as targets for validating the efficacy of future therapeutic strategies aiming to delay and/or revert the pathologic phenotype of PXE fibroblasts. Moreover, data open new perspectives for investigating PXE-like phenotypes in the absence of ABCC6 mutations.