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Published on: June 3, 2018
MiR-132 Regulates Rem Expression in Cardiomyocytes During Long-Term β-Adrenoceptor Agonism
Elba D Carrillo1, Raúl Sampieri, Ascención Hernández
1Departamento de Farmacología. Centro de Investigación y de Estudios Avanzados del I.P.N. México, D.F. 07360. México.
Aims:
To characterize the effects of long-term β-adrenergic receptor stimulation on Rem protein and mRNA expression in rat heart and possible involvement of miR-132.
Methods:
Adult rats were treated with isoproterenol (ISO, 150 µg.kg.h(-1)) for 2 d and Rem, miR-132, and α1c (the principal subunit of Cav1.2 channels) were measured at protein and mRNA levels with western blot and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) experiments, respectively. Ca(2+) currents and intracellular Ca(2+) signals were evaluated in isolated cardiomyocytes.
Results:
Systemic administration of ISO led to decreases in Rem protein and mRNA levels (down to 49%). Furthermore, levels of the microRNAs (miRs) miR-132 and miR-214 were upregulated 5- and 9-fold, respectively. Transfection of miR-132, but not miR-214, into HEK293 cells reduced the expression of a luciferase reporter gene controlled by a conserved 3´-untranslated region (UTR) of Rem by half. Chronic ISO administration also led to a 25% decrease in the amplitude of peak L-type Ca(2+) currents, a 40% decrease in α1c subunit protein abundance at the membrane level, and a 60% decrease in expression of α1c channel subunit mRNA.
Conclusions:
These results suggest that Rem expression is down-regulated posttranscriptionally by miR-132 in response to long-term activation of β-adrenergic signaling, but this down-regulation does not produce a larger Ca(2+) influx through Cav1.2 channels.
Insights
Long-term beta-adrenergic stimulation down-regulates Rem expression via miR-132 in rat hearts. This does not significantly alter Cav1.2 channel function.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Pharmacology
Background:
- Beta-adrenergic receptor (β-AR) signaling plays a critical role in cardiac function.
- Rem protein and its regulation are implicated in cardiac remodeling.
- MicroRNAs (miRs) are emerging as key regulators of gene expression in the heart.
Purpose of the Study:
- To investigate the impact of chronic β-adrenergic stimulation on Rem expression in the rat heart.
- To explore the potential role of miR-132 in mediating these effects.
- To assess the functional consequences on Cav1.2 calcium channels.
Main Methods:
- Adult rats were treated with isoproterenol (ISO) to simulate long-term β-adrenergic stimulation.
- Rem, miR-132, and α1c subunit (Cav1.2 channel) expression were quantified using Western blot and qRT-PCR.
- Electrophysiological studies (Ca(2+) currents) were performed in isolated cardiomyocytes.
Main Results:
- Isoproterenol treatment significantly decreased Rem protein and mRNA levels.
- miR-132 and miR-214 levels were markedly upregulated following ISO administration.
- miR-132 directly targeted Rem, reducing its expression, while Cav1.2 channel function and α1c subunit abundance were reduced.
Conclusions:
- Rem expression is post-transcriptionally downregulated by miR-132 in response to chronic β-adrenergic signaling.
- Despite Rem downregulation, significant alterations in Cav1.2 channel influx were not observed.
- These findings elucidate a novel regulatory pathway involving miR-132 and Rem in the context of β-adrenergic signaling in the heart.
