De León Héctor, Boué Stéphanie, Schlage Walter K, Boukharov Natalia, Westra Jurjen W, Gebel Stephan, VanHooser Aaron, Talikka Marja, Fields R Brett, Veljkovic Emilija, Peck Michael J, Mathis Carole, Hoang Vy, Poussin Carine, Deehan Renee, Stolle Katrin, Hoeng Julia, Peitsch Manuel C
Philip Morris International R&D, Philip Morris Products S,A,, Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
J Transl Med. 2014 Jun 26;12:185. doi: 10.1186/1479-5876-12-185.
Numerous inflammation-related pathways have been shown to play important roles in atherogenesis. Rapid and efficient assessment of the relative influence of each of those pathways is a challenge in the era of "omics" data generation. The aim of the present work was to develop a network model of inflammation-related molecular pathways underlying vascular disease to assess the degree of translatability of preclinical molecular data to the human clinical setting.
We constructed and evaluated the Vascular Inflammatory Processes Network (V-IPN), a model representing a collection of vascular processes modulated by inflammatory stimuli that lead to the development of atherosclerosis.
Utilizing the V-IPN as a platform for biological discovery, we have identified key vascular processes and mechanisms captured by gene expression profiling data from four independent datasets from human endothelial cells (ECs) and human and murine intact vessels. Primary ECs in culture from multiple donors revealed a richer mapping of mechanisms identified by the V-IPN compared to an immortalized EC line. Furthermore, an evaluation of gene expression datasets from aortas of old ApoE-/- mice (78 weeks) and human coronary arteries with advanced atherosclerotic lesions identified significant commonalities in the two species, as well as several mechanisms specific to human arteries that are consistent with the development of unstable atherosclerotic plaques.
We have generated a new biological network model of atherogenic processes that demonstrates the power of network analysis to advance integrative, systems biology-based knowledge of cross-species translatability, plaque development and potential mechanisms leading to plaque instability.
众多炎症相关通路已被证明在动脉粥样硬化形成过程中发挥重要作用。在“组学”数据生成的时代，快速有效地评估每条通路的相对影响是一项挑战。本研究的目的是建立一个血管疾病潜在的炎症相关分子通路网络模型，以评估临床前分子数据向人类临床环境转化的程度。
我们构建并评估了血管炎症过程网络（V-IPN），该模型代表了由炎症刺激调节的一系列血管过程，这些过程导致动脉粥样硬化的发展。
利用V-IPN作为生物学发现的平台，我们从来自人类内皮细胞（ECs）以及人类和小鼠完整血管的四个独立数据集中，通过基因表达谱数据确定了关键的血管过程和机制。与永生化EC系相比，来自多个供体的原代培养ECs显示出由V-IPN确定的机制的更丰富映射。此外，对老年ApoE-/-小鼠（78周）主动脉和具有晚期动脉粥样硬化病变的人类冠状动脉的基因表达数据集进行评估，确定了这两个物种之间的显著共性，以及一些与人类动脉特异性相关的机制，这些机制与不稳定动脉粥样硬化斑块的发展一致。
我们生成了一个新的动脉粥样硬化形成过程的生物网络模型，该模型展示了网络分析在推进基于系统生物学的跨物种可转化性、斑块发展以及导致斑块不稳定的潜在机制的综合知识方面的能力。
