Laboratoire de Physique Théorique, Université de Toulouse, CNRS, UPS, 31062 Toulouse, France.
Clarivate Analytics, 08025 Barcelona, Spain.
Biomolecules. 2024 Oct 31;14(11):1395. doi: 10.3390/biom14111395.
Myocardial fibrosis is a major pathologic disorder associated with a multitude of cardiovascular diseases (CVD). The pathogenesis is complex and encompasses multiple molecular pathways. Integration of fibrosis-associated genes into the global MetaCore network of protein-protein interactions (PPI) offers opportunities to identify PPI with functional and therapeutic significance. Here, we report the generation of a fibrosis-focused PPI network and identification of fibroblast-specific arbitrators driving reparative and reactive myocardial fibrosis. In TGF-β-mediated fibroblast activation, developed network analysis predicts new regulatory mechanisms for fibrosis-associated genes. We introduce an efficient Erdös barrage approach to suppress activation of a number of fibrosis-associated nodes in order to reverse fibrotic cascades. In the network model each protein node is characterized by an Ising up or down spin corresponding to activated or repairing state acting on other nodes being initially in a neutral state. An asynchronous Monte Carlo process describes fibrosis progression determined by a dominant action of linked proteins. Our results suggest that the constructed Ising Network Fibrosis Interaction model offers network insights into fibrosis mechanisms and can complement future experimental efforts to counteract cardiac fibrosis.
心肌纤维化是与多种心血管疾病（CVD）相关的主要病理紊乱。其发病机制复杂，涉及多个分子途径。将纤维化相关基因整合到全局 MetaCore 蛋白质-蛋白质相互作用（PPI）网络中，为识别具有功能和治疗意义的 PPI 提供了机会。在这里，我们报告了一个专注于纤维化的 PPI 网络的生成，并确定了驱动修复性和反应性心肌纤维化的成纤维细胞特异性仲裁者。在 TGF-β介导的成纤维细胞激活中，开发的网络分析预测了纤维化相关基因的新调控机制。我们引入了一种有效的厄多斯障碍方法来抑制大量纤维化相关节点的激活，以逆转纤维化级联。在网络模型中，每个蛋白质节点的特征是一个 Ising 上或下的自旋，对应于处于激活或修复状态的节点对处于初始中性状态的其他节点的作用。异步蒙特卡罗过程描述了由连接蛋白的主导作用决定的纤维化进展。我们的结果表明，构建的 Ising Network Fibrosis Interaction 模型为纤维化机制提供了网络见解，并可以补充未来对抗心脏纤维化的实验努力。
