Nonbiased Molecular Screening Identifies Novel Molecular Regulators of Fibrogenic and Proliferative Signaling in Myxomatous Mitral Valve Disease.
Nonbiased Molecular Screening Identifies Novel Molecular Regulators of Fibrogenic and Proliferative Signaling in Myxomatous Mitral Valve Disease.
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DOI：
10.1161/circgenetics.114.000921
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发表时间：
2015-06
期刊：
影响因子：
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通讯作者：
Miller JD
中科院分区：
文献类型：
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作者：
Thalji NM;Hagler MA;Zhang H;Casaclang-Verzosa G;Nair AA;Suri RM;Miller JD
粘液瘤性二尖瓣退行性变（MMVD）的病理过程仍然知之甚少。我们试图确定新的机制有助于这种情况的发展。微阵列用于测量11个粘液瘤和11个非粘液瘤人类二尖瓣的基因表达。使用qRT-PCR和免疫组织化学确认差异基因表达（阈值p<0.05;倍数变化>1.5）和途径激活（不稳定性）。在体外评估BMP 4和TGF-β2对差异基因表达的贡献。在小鼠体内检查血管紧张素-II对差异途径活化的贡献。2，602个基因在粘液瘤性和非粘液瘤性瓣膜之间差异表达。由于配体表达增加和SMAD 2/3信号转导去抑制，MMVD中典型TGF-β信号转导增加，并通过qRT-PCR和免疫组织化学证实。粘液瘤瓣膜显示典型BMP和Wnt/β-连环蛋白信号传导的激活以及它们共同靶点Runx 2的上调。我们的数据集提供了转录和免疫组织化学证据激活免疫细胞浸润。在体外，用TGF-β2处理二尖瓣间质细胞在mRNA和蛋白水平上增加了β-catenin信号传导，表明TGF-β2和Wnt信号传导之间存在相互作用。在小鼠体内输注血管紧张素-II重新捕获了人MMVD信号通路特征的几个变化。这些数据支持一种新的疾病框架，即TGF-β2、BMP 4、Wnt/β-连环蛋白或免疫信号传导的激活在MMVD的发病机制中起主要作用。我们提出这些途径以依赖于环境的方式作用，以驱动与主动脉瓣疾病中观察到的表型变化根本不同的表型变化，并开辟了指导未来MMVD发病机制研究的新途径。
Pathological processes underlying myxomatous mitral valve degeneration (MMVD) remain poorly understood. We sought to identify novel mechanisms contributing to development of this condition. Microarrays were used to measure gene expression in 11 myxomatous and 11 non-myxomatous human mitral valves. Differential gene expression (thresholds p<0.05; fold-change>1.5) and pathway activation (Ingenuity) were confirmed using qRT-PCR and immunohistochemistry. Contributions of BMP4 and TGF-β2 to differential gene expression were evaluated in vitro. Contributions of angiotensin-II to differential pathway activation were examined in mice in vivo. 2,602 genes were differentially expressed between myxomatous and non-myxomatous valves. Canonical TGF-β signaling was increased in MMVD due to increased ligand expression and de-repression of SMAD2/3 signaling and was confirmed with qRT-PCR and immunohistochemistry. Myxomatous valves demonstrated activation of canonical BMP and Wnt/β-catenin signaling and upregulation of their common target Runx2. Our dataset provided transcriptional and immunohistochemical evidence for activated immune cell infiltration. In vitro treatment of mitral valve interstitial cells with TGF-β2 increased β-catenin signaling at mRNA and protein levels, suggesting interactions between TGF-β2 and Wnt signaling. In vivo infusion of mice with angiotensin-II recaptured several changes in signaling pathways characteristic of human MMVD. These data support a new disease framework whereby activation of TGF-β2, BMP4, Wnt/β-catenin, or immune signaling play major roles in the pathogenesis of MMVD. We propose these pathways act in a context-dependent manner to drive phenotypic changes that fundamentally differ from those observed in aortic valve disease, and open novel avenues guiding future research into the pathogenesis of MMVD.