Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach.
Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach.
复制标题
DOI：
10.1038/s41540-017-0013-4
复制
发表时间：
2017
影响因子：
4
通讯作者：
Bayes-Genis A
中科院分区：
文献类型：
--
作者：
Iborra-Egea O;Gálvez-Montón C;Roura S;Perea-Gil I;Prat-Vidal C;Soler-Botija C;Bayes-Genis A
沙库巴曲/缬沙坦，被证明优于其他传统的心力衰竭管理治疗，但其作用机制仍不清楚。在这项研究中，我们试图探索沙库巴曲/缬沙坦在心力衰竭和心肌梗死后重塑的机制细节，使用计算机，系统生物学方法。分析响应于猪的心肌梗死而获得的心肌转录组以解决梗死后心室重构。使用Reciprocal Best（blast）Hits、Gene Name Correspondence和InParanoid数据库将猪转录组命中映射到其人类等同物。使用基因表达综合数据库（登录号GSE 57345，子系列GSE 57338）中可用的公共数据研究心力衰竭重塑，使用GEO 2 R工具处理。使用治疗性能映射系统技术，生成了经过训练以符合一组分子标准的专用数学模型，这些分子标准定义了两种病理学并包括沙库巴曲/缬沙坦的所有可用信息。所有纳入生物网络的关系都来自公共资源（包括KEGG、REACTOME、INTACT、BIOGRID和MINT）。人工神经网络分析显示，沙库巴曲/缬沙坦协同作用，通过8个主要的协同节点，对心肌细胞死亡和左心室细胞外基质重塑。当独立研究每种途径时，发现缬沙坦通过抑制鸟嘌呤核苷酸结合蛋白家族的成员来改善心脏重塑，而沙库巴曲通过抑制PTEN来减轻心肌细胞死亡、肥大和心肌细胞收缩力受损。本研究采用系统生物学方法探讨沙库巴曲/缬沙坦对心肌梗死和心力衰竭后心脏重构的复杂分子作用机制。此外，该数据集提供了使用沙库巴曲/缬沙坦预防梗死后重塑的病理生理学原理。治疗心力衰竭的新药沙库比曲/缬沙坦通过防止心脏扩张来恢复心脏活力。使用来自心肌梗死和心力衰竭样本的数据，我们生成了一个数学模型，以更好地理解沙库巴曲/缬沙坦如何调节病理性心脏大小以及药物的联合作用。我们的分析表明，沙库巴曲/缬沙坦主要通过阻断细胞死亡和心脏细胞外膜的病理改变来起作用。这两个主要过程发生在心脏病发作后。最重要的是，我们发现了8种蛋白质的核心，它们在这一过程中发挥了关键作用。在最基本的水平上更好地理解新型心血管药物的作用机制可能有助于解释未来的治疗和适应症。
Sacubitril/Valsartan, proved superiority over other conventional heart failure management treatments, but its mechanisms of action remains obscure. In this study, we sought to explore the mechanistic details for Sacubitril/Valsartan in heart failure and post-myocardial infarction remodeling, using an in silico, systems biology approach. Myocardial transcriptome obtained in response to myocardial infarction in swine was analyzed to address post-infarction ventricular remodeling. Swine transcriptome hits were mapped to their human equivalents using Reciprocal Best (blast) Hits, Gene Name Correspondence, and InParanoid database. Heart failure remodeling was studied using public data available in gene expression omnibus (accession GSE57345, subseries GSE57338), processed using the GEO2R tool. Using the Therapeutic Performance Mapping System technology, dedicated mathematical models trained to fit a set of molecular criteria, defining both pathologies and including all the information available on Sacubitril/Valsartan, were generated. All relationships incorporated into the biological network were drawn from public resources (including KEGG, REACTOME, INTACT, BIOGRID, and MINT). An artificial neural network analysis revealed that Sacubitril/Valsartan acts synergistically against cardiomyocyte cell death and left ventricular extracellular matrix remodeling via eight principal synergistic nodes. When studying each pathway independently, Valsartan was found to improve cardiac remodeling by inhibiting members of the guanine nucleotide-binding protein family, while Sacubitril attenuated cardiomyocyte cell death, hypertrophy, and impaired myocyte contractility by inhibiting PTEN. The complex molecular mechanisms of action of Sacubitril/Valsartan upon post-myocardial infarction and heart failure cardiac remodeling were delineated using a systems biology approach. Further, this dataset provides pathophysiological rationale for the use of Sacubitril/Valsartan to prevent post-infarct remodeling. The new wonder drug in heart failure management, Sacubitril/Valsartan, rejuvenates the heart by preventing its dilation. Using data from myocardial infarction and heart failure samples, we generated a mathematical model to better understand how Sacubitril/Valsartan modulates pathological heart resize and the combined effect of the drug. Our analysis revealed that Sacubitril/Valsartan mainly acts by blocking both, cell death and the pathological makeover of the outer-membrane of the cardiac cells. These two major processes occur after a heart attack. Most importantly, we discovered a core of 8 proteins that emerge as key players in this process. A better understanding of the mechanism of novel cardiovascular drugs at the most basic level may help decipher future therapies and indications.