# Fibroblast-Specific Protein Interactions for Myocardial Fibrosis from MetaCore Network
## 4 Discussion and Conclusions  
Decoding fibrosis-associated proteins and fibrotic remodeling progression is a critical issue in treating heart failure. An experimental determination of the fibrosis resolution is extremely time consuming and dynamic process. In this work we present and describe a mathematical model of the fibrosis progression using the global PPI MetaCore network. The performed analysis shows that in TGF\(\beta\)-mediated fibroblast activation, PPI hubs predict new regulatory proteins for fibrosis progression. We developed an efficient method of the Erd'os barrage to identify the proteins driving fibrosis activation cascades in a physiopathological scenario using MetaCore network. In cardiac tissue, resident cardiac fibroblasts respond to stress or injury by evoluting through phases determined by a inflammatory motifs, a proliferative capacity, and finally, a reparative status, characterized by the deposition of ECM that culminates in fibrosis. The molecular mechanisms orchestrating the dynamic control of the fibroblast phenotype remain obscure, hampering the development of therapeutic strategies to combat cardiac fibrosis. In our study, we found that c-Myc, p53, c-Fos and Androgen receptor arbitrate cardiac fibroblast activation in cardiac remodeling. The gene encoding the c-MYC is the most frequently perturbed transcription factor in the majority of human cancers, with its activation of downstream target genes in the vast majority of the cancer types [37]. Dysfunction of c-MYC can occur through elevated transcription of the gene, amplification or protein stabilization, all of which release the otherwise tight control and altered expression levels of the protein in the cell [38]. nhibition of c-MYC has been observed to favor apoptosis, growth arrest, differentiation, senescence, metabolic changes and tumour regression in several human cancer models, clearly reflecting its potential as a target for anti-cancer therapy [39]. In activated cardiac fibroblasts, p53 transcriptional targets are among the most deregulated gene programs in pressure overload-induced tissue remodeling [40]. In cancerous tumors, p53 is an important component of the DNA damage and transcriptional regulator of cell cycle [41]. Interestingly, p53-sensitive cellular senescence has also been linked to myocardial remodeling in animal models ou tissue fibrosis [42]. Indeed, over expression of the p53 target gene in transgenic mice inhibits fibroblast activation and reduces scar formation after myocardial infarction [43]. An important factor C-fos is a member of a family of early genes which are involved in the signal transduction cascade coupling extracellular stimuli to intracellular events [44]. In particular, C-fos is critical to the regulation of transcription, and may mediate long-term effects of growth factors and membrane-depolarising signals on neural responses to stress [45]. Androgen receptor (AR) signalling in fibroblasts is important in carcinogenesis and prostate development [46]. However, the molecular mechanisms of AR action in fibroblasts and other non-cardiac cell types are largely unknown. In the past few years, the receptors and signal transduction pathways mediating the effects of TGF-\(\beta\) on fibroblasts have been identified, enabling the dissection of the specific pathways involved in pathogenic events. TGF-\(\beta\) type I and type II transmembrane receptor serine/threonine kinases transduce downstream signals via novel cytoplasmic latent transcription factors, Smad proteins [47]. Both Smad2 and Smad3 are phosphorylated directly by the type I receptor kinase and able to translocate to the nucleus, where they act as transcriptional regulators of target genes controlling cell apoptosis and differentiation [48]. Interestingly, deletion of Smad3 results primarily in impaired status of immunity in mice and shortening their lifespan [49]. The Smad pathway is believed to be the major signaling mechanism through which active TGF-\(\beta\) stimulates the induction of profibrotic cascades.