Discovery of Natural Compounds for Cardiac Fibrosis by a Transcriptome-Based Functional Gene Module Reference Approach

Anti-cardiac fibrosis (CF) is one
of the key therapeutic strategies
for the treatment of various heart diseases. Therefore, development
of drugs targeting CF is promising. However, there are very few studies
that systemically explore effective drugs for CF. It has been known
that many natural compounds display antifibrosis effects. In this
work, we aim to build an integrated model for systematic pursuit of
anti-CF agents from natural compounds. We first constructed a heart-specific
CF marker-gene-centered functional gene module (HCFM) that represents
a set of genes specifically involved in CF based on the CF marker
genes and known gene coexpression knowledge. Then, we extracted transcriptional
data induced by natural compounds from the Gene Expression Omnibus
database. The anti-CF effects of compounds were evaluated by the correlation
of HCFM in the compound-induced gene expression profiles by gene set
enrichment analysis. Finally, the anti-CF effect of a top-predicted
natural monomer, schisantherin A, was experimentally validated in
the myocardial infarction animal model. This strategy integrating
different types of technologies is expected to help create new opportunities
for development of drugs targeting CF.