Department of Genetics and Genomic Sciences (I.F., B.R., L.A., S.K., J.T.D., C.G., J.L.M.B., I.P.), Icahn School of Medicine at Mount Sinai, New York, NY.
Icahn Institute for Data Science and Genomic Technology (B.R., J.T.D., J.L.M.B., I.P.), Icahn School of Medicine at Mount Sinai, New York, NY.
Circ Genom Precis Med. 2019 Jun;12(6):e002390. doi: 10.1161/CIRCGEN.118.002390. Epub 2019 May 6.
Antiretroviral therapy (ART) for HIV infection increases risk for coronary artery disease (CAD), presumably by causing dyslipidemia and increased atherosclerosis. We applied systems pharmacology to identify and validate specific regulatory gene networks through which ART drugs may promote CAD.
Transcriptional responses of human cell lines to 15 ART drugs retrieved from the Library of Integrated Cellular Signatures (overall 1127 experiments) were used to establish consensus ART gene/transcriptional signatures. Next, enrichments of differentially expressed genes and gene-gene connectivity within these ART-consensus signatures were sought in 30 regulatory gene networks associated with CAD and CAD-related phenotypes in the Stockholm Atherosclerosis Gene Expression study.
Ten of 15 ART signatures were significantly enriched both for differential expression and connectivity in a specific atherosclerotic arterial wall regulatory gene network (AR-RGN) causal for CAD involving RNA processing genes. An atherosclerosis in vitro model of cholestryl ester-loaded foam cells was then used for experimental validation. Treatments of these foam cells with ritonavir, nelfinavir, and saquinavir at least doubled cholestryl ester accumulation ( P=0.02, 0.0009, and 0.02, respectively), whereas RNA silencing of the AR-RGN top key driver, PQBP1 (polyglutamine binding protein 1), significantly curbed cholestryl ester accumulation following treatment with any of these ART drugs by >37% ( P<0.05).
By applying a novel systems pharmacology data analysis framework, 3 commonly used ARTs (ritonavir, nelfinavir, and saquinavir) were found altering the activity of AR-RGN, a regulatory gene network promoting foam cell formation and risk of CAD. Targeting AR-RGN or its top key driver PQBP1 may help reduce CAD side effects of these ART drugs.
抗逆转录病毒疗法（ART）治疗 HIV 感染会增加患冠状动脉疾病（CAD）的风险，这可能是由于引起血脂异常和动脉粥样硬化增加所致。我们应用系统药理学来鉴定和验证特定的调节基因网络，ART 药物可能通过这些基因网络促进 CAD 的发生。
从综合细胞信号库（总共 1127 个实验）中检索了 15 种 ART 药物，用于建立人类细胞系对这些药物的转录反应共识 ART 基因/转录特征。接下来，在与 STOCKHOLM 动脉粥样硬化基因表达研究中的 CAD 和 CAD 相关表型相关的 30 个调节基因网络中，寻找这些 ART 一致性特征中差异表达基因和基因-基因连接的富集。
在涉及 RNA 处理基因的特定动脉粥样硬化血管壁调节基因网络（AR-RGN）中，15 个 ART 特征中有 10 个在差异表达和连接方面均显著富集，该基因网络是导致 CAD 的原因。然后，使用载有胆固醇酯的泡沫细胞体外动脉粥样硬化模型进行实验验证。用利托那韦、奈非那韦和沙奎那韦处理这些泡沫细胞，至少使胆固醇酯的积累增加了两倍（P=0.02、0.0009 和 0.02），而针对 AR-RGN 的顶级关键驱动基因 PQBP1（多聚谷氨酰胺结合蛋白 1）的 RNA 沉默，在用任何一种这些 ART 药物处理后，显著地将胆固醇酯的积累减少了 37%以上（P<0.05）。
通过应用一种新的系统药理学数据分析框架，发现了 3 种常用的 ARTs（利托那韦、奈非那韦和沙奎那韦）改变了 AR-RGN 的活性，AR-RGN 是一种促进泡沫细胞形成和 CAD 风险的调节基因网络。针对 AR-RGN 或其顶级关键驱动基因 PQBP1，可能有助于降低这些 ART 药物治疗 CAD 的副作用。
