# BRG1 exacerbates myocardial fibrosis after myocardial infarction by interacting with ZEB1

## TL;DR

This study shows that BRG1 worsens heart scarring after a heart attack by working with ZEB1 to block a protective protein, suggesting BRG1 could be a target for new treatments.

## Contribution

The study identifies a new BRG1/ZEB1/PP2A pathway that drives heart fibrosis after myocardial infarction.

## Key findings

- BRG1 is upregulated in fibrotic mouse hearts and activated cardiac fibroblasts after MI.
- BRG1 interacts with ZEB1 to repress Ppp2r1a, reducing PP2A activity and enhancing Smad3 phosphorylation.
- BRG1 knockdown reduces fibrosis and improves heart function in mice and human cardiac fibroblasts.

## Abstract

Myocardial fibrosis, characterized by excessive collagen deposition and fibroblast activation, is a pivotal pathological process driving heart failure after myocardial infarction (MI). Our prior research revealed that Brahma-related gene 1 (BRG1) expression is elevated after MI and exacerbated cardiac electrophysiological remodeling; however, its precise role and molecular mechanism in post-MI fibrosis remain undefined.

BRG1 expression was assessed in a mouse MI model and in TGF-β1-stimulated cardiac fibroblasts (CFs). Gain- and loss-of-function studies were performed using adenoviral vectors, siRNA, and plasmids in vitro and in vivo. Cardiac function and fibrosis were evaluated by echocardiography and histology. The molecular mechanism was dissected through co-immunoprecipitation (Co-IP), dual-luciferase reporter assays, chromatin immunoprecipitation (ChIP), and functional rescue experiments targeting the PP2A/Smad3 axis.

BRG1 was upregulated in fibrotic mouse hearts post-MI and in activated CFs. In vivo, BRG1 knockdown via AAV9-shRNA improved cardiac function, reduced infarct size, and attenuated fibrosis. In vitro, BRG1 promoted CFs proliferation, migration, and collagen production. Mechanistically, TGF-β1 enhanced the interaction between BRG1 and the transcription factor ZEB1. This complex transcriptionally repressed Ppp2r1a, the gene encoding the PP2A structural subunit Aα, leading to diminished PP2A activity. Consequently, Smad3 phosphorylation and nuclear translocation were enhanced, amplifying the pro-fibrotic TGF-β/Smad3 cascade. Crucially, ZEB1 knockdown or PP2A inhibition (okadaic acid) could respectively block or rescue the fibrotic effects of BRG1. Finally, BRG1 knockdown similarly suppressed fibrotic activation in human CFs.

Our study defines a novel BRG1/ZEB1/PP2A transcriptional axis as a key driver of myocardial fibrosis and suggests BRG1 as a potential therapeutic target for mitigating fibrotic remodeling after MI.