MiR-150 blunts cardiac dysfunction in mice with cardiomyocyte loss of β1-adrenergic receptor/β-arrestin signaling and controls a unique transcriptome
Related Experiment Video
Updated: Aug 15, 2025
Author Spotlight: Cardiac Cell Transgenesis for Rapid Gene Screening
Published on: May 24, 2024
Bruno Moukette1, Satoshi Kawaguchi1, Marisa N Sepulveda1
1Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
Insights
MicroRNA-150 (miR-150) protects heart cells and improves cardiac function after heart attack. This study shows miR-150 rescues heart dysfunction by regulating specific non-coding RNAs and genes.
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- The β1-adrenergic receptor (β1AR) signaling pathway in cardiomyocytes (CMs) is crucial for heart protection.
- β-arrestin-mediated β1AR signaling promotes CM survival and is linked to microRNA-150 (miR-150) upregulation.
- CM miR-150 has been shown to inhibit maladaptive cardiac remodeling post-myocardial infarction.
Purpose of the Study:
- To investigate if miR-150 can rescue cardiac dysfunction in mice with impaired β-arrestin-mediated β1AR signaling in CMs.
- To identify novel non-coding RNA (ncRNA) and gene regulatory mechanisms involved in β1AR/β-arrestin signaling and miR-150's cardioprotective effects.
Main Methods:
- Generation of a double transgenic (TG) mouse model with CM-specific β1AR mutation (GRK⁻β1AR) and miR-150 overexpression.
- Assessment of cardiac function following chronic catecholamine stimulation in TG mice.
- Genome-wide profiling of circular RNA, long noncoding RNA (lncRNA), and mRNA.
Main Results:
- Overexpression of miR-150 improved cardiac dysfunction in mice with impaired β-arrestin-mediated β1AR signaling.
- Identification of novel cardiac ncRNAs and genes regulated by β1AR/β-arrestin signaling and miR-150.
- lncRNA Gm41664 and GDAP1L1 were identified as upstream and downstream regulators of miR-150, respectively.
Conclusions:
- miR-150 is sufficient to rescue cardiac dysfunction in the absence of normal β-arrestin-mediated β1AR signaling.
- miR-150 exerts cardioprotective effects by repressing the pro-apoptotic gene GDAP1L1 and is influenced by Gm41664.
- These findings highlight miR-150's significant role in β1AR/β-arrestin-mediated cardioprotection via unique ncRNA and gene regulation in CMs.
Abstract:
The β1-adrenergic receptor (β1AR) is found primarily in hearts (mainly in cardiomyocytes [CMs]) and β-arrestin-mediated β1AR signaling elicits cardioprotection through CM survival. We showed that microRNA-150 (miR-150) is upregulated by β-arrestin-mediated β1AR signaling and that CM miR-150 inhibits maladaptive remodeling post-myocardial infarction. Here, we investigate whether miR-150 rescues cardiac dysfunction in mice bearing CM-specific abrogation of β-arrestin-mediated β1AR signaling. Using CM-specific transgenic (TG) mice expressing a mutant β1AR (G protein-coupled receptor kinase [GRK]-β1AR that exhibits impairment in β-arrestin-mediated β1AR signaling), we first generate a novel double TG mouse line overexpressing miR-150. We demonstrate that miR-150 is sufficient to improve cardiac dysfunction in CM-specific GRK-β1AR TG mice following chronic catecholamine stimulation. Our genome-wide circular RNA, long noncoding RNA (lncRNA), and mRNA profiling analyses unveil a subset of cardiac ncRNAs and genes as heretofore unrecognized mechanisms for beneficial actions of β1AR/β-arrestin signaling or miR-150. We further show that lncRNA Gm41664 and GDAP1L1 are direct novel upstream and downstream regulators of miR-150. Lastly, CM protective actions of miR-150 are attributed to repressing pro-apoptotic GDAP1L1 and are mitigated by pro-apoptotic Gm41664. Our findings support the idea that miR-150 contributes significantly to β1AR/β-arrestin-mediated cardioprotection by regulating unique ncRNA and gene signatures in CMs.
