# BACH2 links β1-adrenergic receptor/β-arrestin1 signaling to MIAT to inhibit cardiac fibroblast activation and cardiomyocyte apoptosis

## TL;DR

This study shows how a noncoding RNA called MIAT is regulated by a signaling pathway involving BACH2 and beta-adrenergic receptors, which helps prevent heart damage after a heart attack.

## Contribution

The study identifies a novel regulatory axis linking β1-adrenergic receptor/β-arrestin1 signaling, BACH2, and MIAT in cardiac remodeling.

## Key findings

- BACH2 forms a nuclear complex with β-arrestin1 and binds to the MIAT promoter.
- BACH2 represses MIAT expression, inhibiting cardiac fibroblast activation and cardiomyocyte apoptosis.
- Carvedilol downregulates MIAT via β1-adrenergic receptor/β-arrestin1 signaling and upregulates BACH2.

## Abstract

The myocardial infarction-associated transcript (MIAT), a conserved long noncoding RNA, is upregulated in failing human and murine hearts. We previously demonstrated that systemic or cardiomyocyte (CM)-restricted ablation of MIAT in mice attenuated maladaptive cardiac remodeling following myocardial infarction by suppressing the expression of proapoptotic and profibrotic genes. Despite growing evidence from human and rodent studies implicating MIAT in heart failure, the upstream regulatory pathways controlling its expression remain poorly defined. We hypothesized that MIAT is regulated either by β-arrestin1-mediated β1-adrenergic receptor protective signaling or by the transcription factor BTB domain and CNC homolog 2 (BACH2), which is downregulated in failing human and murine hearts. In this study, we show that treatment with the β-blocker carvedilol downregulates cardiac MIAT via β1-adrenergic receptor/β-arrestin1 signaling and concurrently upregulates BACH2. Mechanistically, our co-immunoprecipitation and electrophoretic mobility shift assays reveal that BACH2 forms a nuclear complex with β-arrestin1 and binds to conserved elements within the MIAT promoter. Using primary adult human cardiac fibroblasts (CFs) as well as human and rodent CMs, we further show that BACH2 represses profibrotic and proapoptotic MIAT expression, thereby inhibiting CF activation and CM apoptosis. Together, these findings identify a novel regulatory axis involving β1-adrenergic receptor/β-arrestin1 signaling, BACH2, and MIAT, highlighting its critical role in maladaptive cardiac remodeling.