Functional Gene Module-Based Identification of Phillyrin as an Anticardiac Fibrosis Agent

Abstract

Cardiac fibrosis (CF) greatly influences the therapeutic effects of heart diseases and remains an urgent challenge in clinical therapy. Till now, only a few methods are used to find potential anti-CF drugs effectively. This study aimed to construct a gene functional module to represent the core pathological process of CF and screen antifibrotic agents capable of decreasing the expression of the gene functional module. First, three CF marker genes Postn, Ddr2, and Pdgfra were selected to identify the corresponding highest coexpressed genes in the genome-based transcriptional profiles of human hearts. Both the marker genes and the coexpressed genes formed the CF-related gene functional module. Second, the correlation of the module with the CF process was measured in a collection of gene expression profiles of heart diseases to evaluate the participation of the functional module in heart diseases. Third, the anti-CF effects of phillyrin were predicted by the enrichment analysis of the module in the phillyrin-induced transcriptional profile. Finally, the myocardial infarction animal model was used to validate the cardioprotective and anti-CF effects of phillyrin experimentally. The results showed that phillyrin was a novel antifibrotic agent in heart diseases.

Keywords: cardiac fibrosis; gene expression profile; gene set enrichment analysis; marker genes; phillyrin.