PARP9 affects myocardial function through TGF-β/Smad axis and pirfenidone

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Fibrosis Research

Background:

• Cardiac arrhythmias are frequently associated with overactive cardiac fibroblasts (CFs).
• Understanding the role of poly (ADP-ribose) polymerase 9 (PARP9) in Angiotensin II (Ang II)-induced CF activation is crucial.
• Investigating pirfenidone (PFD) as a therapeutic agent for cardiac fibrosis is of significant interest.

Purpose of the Study:

• To identify key genes involved in Ang II-induced CF activation using bioinformatics.
• To evaluate the therapeutic potential of PFD on Ang II-induced CF proliferation, migration, and fibrosis.
• To elucidate the role of PARP9 and the TGF-β/Smad pathway in PFD's mechanism of action.

Main Methods:

• Weighted gene co-expression network analysis (WGCNA), differential gene expression (DEG), protein-protein interaction (PPI), and ROC analysis on the GSE42955 dataset.
• ImmuCellAI tool for assessing immune cell infiltration.
• In vitro experiments assessing CF behavior, fibrosis markers, and signaling pathways under Ang II and PFD treatment, with and without PARP9 overexpression.

Main Results:

• PARP9 was identified as a hub gene with high diagnostic value, associated with immune cell infiltration.
• PFD significantly inhibited Ang II-induced CF proliferation, migration, and fibrosis.
• PFD reduced Ang II-induced PARP9 expression and key fibrosis markers (TGF-β, collagen I, collagen III, α-SMA), and modulated the TGF-β/Smad pathway.

Conclusions:

• PFD demonstrates significant therapeutic effects against Ang II-induced cardiac fibroblast activation and myocardial fibrosis.
• PARP9 plays a critical role in Ang II-induced fibrosis and is a target of PFD.
• PFD modulates the TGF-β/Smad signaling pathway and PARP9 expression, presenting a promising therapeutic strategy for myocardial fibrosis.