Network modeling reveals steps in angiotensin peptide processing.
Network modeling reveals steps in angiotensin peptide processing.
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网络建模揭示了血管紧张素肽加工的步骤。
DOI：
10.1161/hypertensionaha.111.00318
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
Velez,JuanCarlosQ
中科院分区：
文献类型：
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作者：
Schwacke,JohnH;Spainhour,JohnChristianG;Ierardi,JessalynL;Chaves,JoseM;Arthur,JohnM;Janech,MichaelG;Velez,JuanCarlosQ
对肾素-血管紧张素系统(Ang)的新见解改变了我们对该系统的传统看法。然而，这个多肽网络和相关的多肽酶的许多更详细的细节仍然不清楚。我们假设，一种应用于多肽数据的计算系统生物学方法，可以帮助解开酶转化网络。我们从肾素-Ang系统的已建立元素创建的骨架开始，建立并提炼了一个贝叶斯网络模型和一个动态系统模型，并利用在暴露于外源Ang底物的小鼠足细胞中进行的实验的存档基质辅助激光解吸电离飞行时间质谱图进一步开发了该模型。该模型的建立过程提示了先前未知的步骤，其中3个步骤已在体外得到证实，包括neprilysin将Ang(2-10)转化为Ang(2-7)，氨基肽酶A将Ang(1-9)转化为Ang(2-9)，Ang(1-7)转化为Ang(2-7)。这些数据表明neprilysin和氨基肽酶A在肾小球形成生物活性Ang多肽和分流它们的形成中发挥了更广泛的作用。模型还建议了其他步骤，并使用模型比较方法对这些步骤的支持证据进行了评估。我们的结果表明，应用于多肽数据的系统生物学方法在识别Ang肽加工网络中的新步骤方面是有效的，这些发现提高了我们对肾小球肾素-Ang系统的理解。
New insights into the intrarenal renin–angiotensin (Ang) system have modified our traditional view of the system. However, many finer details of this network of peptides and associated peptidases remain unclear. We hypothesized that a computational systems biology approach, applied to peptidomic data, could help to unravel the network of enzymatic conversions. We built and refined a Bayesian network model and a dynamic systems model starting from a skeleton created with established elements of the renin–Ang system and further developed it with archived matrix-assisted laser desorption ionization-time of flight mass spectra from experiments conducted in mouse podocytes exposed to exogenous Ang substrates. The model-building process suggested previously unrecognized steps, 3 of which were confirmed in vitro, including the conversion of Ang(2–10) to Ang(2–7) by neprilysin, Ang(1–9) to Ang(2–9), and Ang(1–7) to Ang(2–7) by aminopeptidase A. These data suggest a wider role of neprilysin and aminopeptidase A in glomerular formation of bioactive Ang peptides and shunting their formation. Other steps were also suggested by the model, and supporting evidence for those steps was evaluated using model-comparison methods. Our results demonstrate that systems biology methods applied to peptidomic data are effective in identifying novel steps in the Ang peptide processing network, and these findings improve our understanding of the glomerular renin–Ang system.