Wang Rui-Sheng, Oldham William M, Loscalzo Joseph
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
New J Phys. 2014 Oct 24;16(10):105014. doi: 10.1088/1367-2630/16/10/105014.
Molecular oxygen is indispensable for cellular viability and function. Hypoxia is a stress condition in which oxygen demand exceeds supply. Low cellular oxygen content induces a number of molecular changes to activate regulatory pathways responsible for increasing the oxygen supply and optimizing cellular metabolism under limited oxygen conditions. Hypoxia plays critical roles in the pathobiology of many diseases, such as cancer, heart failure, myocardial ischemia, stroke, and chronic lung diseases. Although the complicated associations between hypoxia and cardiovascular (and cerebrovascular) diseases (CVD) have been recognized for some time, there are few studies that investigate their biological link from a systems biology perspective. In this study, we integrate hypoxia genes, CVD genes, and the human protein interactome in order to explore the relationship between hypoxia and cardiovascular diseases at a systems level. We show that hypoxia genes are much closer to CVD genes in the human protein interactome than that expected by chance. We also find that hypoxia genes play significant bridging roles in connecting different cardiovascular diseases. We construct an hypoxia-CVD bipartite network and find several interesting hypoxia-CVD modules with significant Gene Ontology (GO) similarity. Finally, we show that hypoxia genes tend to have more CVD interactors in the human interactome than in random networks of matching topology. Based on these observations, we can predict novel genes that may be associated with CVD. This network-based association study gives us a broad view of the relationships between hypoxia and cardiovascular diseases and provides new insights into the role of hypoxia in cardiovascular biology.
分子氧对于细胞的生存能力和功能不可或缺。缺氧是一种应激状态，即氧需求超过供应。细胞内低氧含量会引发一系列分子变化，以激活负责在有限氧条件下增加氧供应和优化细胞代谢的调节途径。缺氧在许多疾病的病理生物学过程中发挥着关键作用，如癌症、心力衰竭、心肌缺血、中风和慢性肺部疾病。尽管缺氧与心血管（及脑血管）疾病（CVD）之间的复杂关联已被认识了一段时间，但从系统生物学角度研究它们生物学联系的研究却很少。在本研究中，我们整合了缺氧基因、CVD基因和人类蛋白质相互作用组，以便在系统层面探索缺氧与心血管疾病之间的关系。我们发现，在人类蛋白质相互作用组中，缺氧基因与CVD基因的距离比随机预期的要近得多。我们还发现，缺氧基因在连接不同心血管疾病方面发挥着重要的桥梁作用。我们构建了一个缺氧 - CVD二分网络，并发现了几个具有显著基因本体（GO）相似性的有趣的缺氧 - CVD模块。最后，我们表明，在人类相互作用组中，缺氧基因比在具有匹配拓扑结构的随机网络中往往有更多的CVD相互作用蛋白。基于这些观察结果，我们可以预测可能与CVD相关的新基因。这项基于网络的关联研究让我们对缺氧与心血管疾病之间的关系有了更广泛的认识，并为缺氧在心血管生物学中的作用提供了新的见解。
