Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
FASEB J. 2020 Aug;34(8):11087-11100. doi: 10.1096/fj.202001062R. Epub 2020 Jul 8.
Ectopic cardiovascular calcification is a highly prevalent pathology for which there are no effective novel or repurposed pharmacotherapeutics to prevent disease progression. We created a human calcification endophenotype module (ie, the "calcificasome") by mapping vascular calcification genes (proteins) to the human vascular smooth muscle-specific protein-protein interactome (218 nodes and 632 edges, P < 10 ). Network proximity analysis was used to demonstrate that the calcificasome overlapped significantly with endophenotype modules governing inflammation, thrombosis, and fibrosis in the human interactome (P < 0.001). A network-based drug repurposing analysis further revealed that everolimus, temsirolimus, and pomalidomide are predicted to target the calcificasome. The efficacy of these agents in limiting calcification was confirmed experimentally by treating human coronary artery smooth muscle cells in an in vitro calcification assay. Each of the drugs affected expression or activity of their predicted target in the network, and decreased calcification significantly (P < 0.009). An integrated network analytical approach identified novel mediators of ectopic cardiovascular calcification and biologically plausible candidate drugs that could be repurposed to target calcification. This methodological framework for drug repurposing has broad applicability to other diseases.
异位心血管钙化是一种高度普遍的病理学，目前尚无有效的新型或重新利用的药物治疗方法来阻止疾病进展。我们通过将血管钙化基因（蛋白质）映射到人类血管平滑肌特异性蛋白质-蛋白质相互作用组，创建了一个人类钙化内表型模块（即“钙化体”）（218 个节点和 632 个边，P < 10 ）。网络接近度分析表明，钙化体与人类相互作用组中控制炎症、血栓形成和纤维化的内表型模块显著重叠（P < 0.001）。基于网络的药物再利用分析进一步表明，依维莫司、替西罗莫司和泊马度胺被预测为靶向钙化体。通过在体外钙化测定中用这些药物处理人冠状动脉平滑肌细胞，实验证实了这些药物在限制钙化方面的疗效。这些药物中的每一种都影响网络中其预测靶标的表达或活性，并显著降低钙化（P < 0.009）。综合网络分析方法确定了异位心血管钙化的新介质和合理的候选药物，这些药物可以被重新用于靶向钙化。这种药物再利用的方法框架具有广泛的适用性，可以应用于其他疾病。
