Fibroblast-Specific Protein-Protein Interactions for Myocardial Fibrosis from MetaCore Network

Abstract

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.