# Fibroblast-Specific Protein Interactions for Myocardial Fibrosis from MetaCore Network
## 1 Introduction  
Myocardial fibrosis is a major pathologic disorder associated with a multitude of cardiovascular diseases (CVD) [1]. In the heart, tissue fibrotic remodeling is characterized by abnormal fibroblast activation and excessive extracellular matrix (ECM) protein accumulation [2]. Although a number of factors have been implicated in orchestrating the fibrotic response, tissue fibrosis is dominated by a central mediator: transforming growth factor-\(\beta\) (TGF-\(\beta\)) [3]. Sustained TGF-\(\beta\) production leads to a continuous cycle of growth factor signaling and deregulated matrix turnover [4]. TGF-\(\beta\) binds a heteromeric receptor complex composed of type I and type II serine/threonine kinase receptors that activate small-dependent gene transcription [5]. The converging lines of evidence suggest that activation of the Smad 3 cascade plays an essential role in extracellular matrix protein gene expression and regulates fibrosis tissue deposition in fibrotic remodeling of the infarcted heart [6]. Abnormalities in TGF-\(\beta\)/Smad3 signaling underlie inflammatory diseases and promote tumor emergence. TGF-\(\beta\) is also central to immune suppression within the tumor microenvironments, and several studies have reported roles in tumor immune evasion and poor responses to cancer immunotherapy [7]. In addition to activation of Smad-dependent signaling, the TGF-\(\beta\) receptor complex can also modulate TGF-\(\beta\)-activated kinase 1 (TAK1 or MAP3K7) [8]. However, despite intensive research, the biomolecules that orchestrate fibrosis are still poorly understood and as a result, effective strategies for limiting fibrosis are lacking [2; 4]. Considering the complex heterogeneity of fibrosis, research strategy on a system-level understanding of the disease using mathematical modeling approaches is a driving force to dissect the complex processes involved in fibrotic disorders. Recently, we have reproduced the classic hallmarks of aberrant cardiac fibroblast activation leading to fibrosis and provided a powerful toolbox for characterization of cardiac fibroblast activation [9]. Although the pathogenesis of fibrotic remodeling has not been well identified, accumulated evidence suggests that multiple genes/proteins and their interactions play important roles in disease scenario [10]. Fibrotic remodeling is a complex process caused by genetic abnormalities that alter protein-protein interactions (PPI) [9; 11]. In the heart, PPI interfaces represent a highly promising, although challenging, class of potential targets for therapeutic options. In fibrosis, PPI form signaling nodes and hubs that transmit pathophysiological cues along molecular networks to achieve an integrated biological output, thereby promoting fibrogenesis and fibrosis progression. Thus, pathway perturbation, through disruption of PPI critical for fibrosis, offers a novel and effective strategy for curtailing the transmission of pro-fibrotic signals. Deciphering of fibrosis-specific PPI would uncover new mechanisms of fibrotic signaling for therapeutic interrogation. Thus a mathematical analysis of the global PPI MetaCore network [12] can provide useful deep insights in the understanding of fibrosis progression processes. In this work we use the PPI MetaCore network [12] to perform a mathematical modeling of fibrosis progression. The results reported in [9] determined the protein pro-fibrotic responses as a feedback on TGF protein stimulation. Thus these results [9] support the known fact that the TGF protein plays an important role in fibrosis tissue [3] and establish proteins with most positive and most negative response in cardiac fibroblasts. A variety of biological applications of the MetaCore network are described in [13; 14]. The general statistical properties of the MetaCore network are presented in [15]. The applications of Google matrix algorithms to the fibrosis PPI based on the MetaCore network are described in [16] using the fibrosis responses obtained in [9].