Manivannan Jeganathan, Prashanth Manjunath, Saravana Kumar Venkatesan, Shairam Manickaraj, Subburaj Jayachandran
AU-KBC Research Centre, MIT Campus-Anna University, Chrompet, Chennai-600044, Tamil Nadu, India.
Tamil Nadu Veterinary and Animal Sciences University, Chennai, Tamil Nadu, India.
Mol Biosyst. 2016 Nov 15;12(12):3683-3694. doi: 10.1039/c6mb00557h.
Since there is no precise therapy for treating vascular calcification by directly targeting the vascular wall, we aim to unveil novel drug targets through mining the molecular effect of a high phosphate environment on vascular cells through computational methods. Here, we hypothesize that manipulation of the vascular pathogenic network by small molecule therapeutics predicted from prior knowledge might offer great promise. With this, we intend to understand the publicly available transcriptomic data of vascular smooth muscle cells and endothelial cells exposed to the high phosphate induced vascular calcification milieu and to re-examine the above published experiments for reasons different from those examined in the previous studies through multilevel systems biological understanding. Hence, in this study the differentially expressed genes were subjected to both upstream and downstream network analysis through multiple standalone software and web servers. To provide an insight into causal signaling, we simultaneously predicted upstream regulatory layers through transcription factor and kinome enrichment analysis. Moreover the possible systems pharmacological choices were presented in three ways as (1) drug induced expression modulation, (2) drugs that interact with upstream and downstream regulatory targets, (3) possible natural product therapeutics from target-compound relationship. Furthermore for validating the current study we have specifically evaluated the preventive effect of two predicted natural compounds in a bovine aortic calcification model. The overall observation predicts a few novel mechanisms that might be involved in vascular dysfunction and calcification in both cell types. Also, the systems pharmacological investigation provides clues for the possible therapeutic options along with validation. In conclusion, the current study indicates that reanalysis of transcriptomic data propels us to reposition the approved drugs and use natural compounds as novel therapeutic agents for vascular calcification.
由于目前尚无通过直接靶向血管壁来治疗血管钙化的精确疗法，我们旨在通过计算方法挖掘高磷环境对血管细胞的分子作用，从而揭示新的药物靶点。在此，我们假设利用先前知识预测的小分子疗法对血管致病网络进行调控可能具有巨大潜力。据此，我们打算了解暴露于高磷诱导的血管钙化环境中的血管平滑肌细胞和内皮细胞的公开转录组数据，并通过多层次系统生物学理解，以与先前研究不同的原因重新审视上述已发表的实验。因此，在本研究中，通过多个独立软件和网络服务器对差异表达基因进行了上下游网络分析。为深入了解因果信号传导，我们通过转录因子和激酶组富集分析同时预测上游调控层。此外，还从三个方面提出了可能的系统药理学选择：（1）药物诱导的表达调节；（2）与上下游调控靶点相互作用的药物；（3）基于靶点 - 化合物关系的可能的天然产物疗法。此外，为验证本研究，我们专门评估了两种预测的天然化合物在牛主动脉钙化模型中的预防作用。总体观察结果预测了一些可能参与两种细胞类型血管功能障碍和钙化的新机制。同时，系统药理学研究为可能的治疗选择提供了线索并进行了验证。总之，当前研究表明，对转录组数据的重新分析促使我们重新定位已批准的药物，并将天然化合物用作血管钙化的新型治疗药物。
