MicroRNA-133 modulates the ß1-adrenergic receptor transduction cascade.
Circ Res
; 115(2): 273-83, 2014 Jul 07.
Article
in En
| MEDLINE
| ID: mdl-24807785
ABSTRACT
RATIONALE The sympathetic nervous system plays a fundamental role in the regulation of myocardial function. During chronic pressure overload, overactivation of the sympathetic nervous system induces the release of catecholamines, which activate ß-adrenergic receptors in cardiomyocytes and lead to increased heart rate and cardiac contractility. However, chronic stimulation of ß-adrenergic receptors leads to impaired cardiac function, and ß-blockers are widely used as therapeutic agents for the treatment of cardiac disease. MicroRNA-133 (miR-133) is highly expressed in the myocardium and is involved in controlling cardiac function through regulation of messenger RNA translation/stability. OBJECTIVE:
To determine whether miR-133 affects ß-adrenergic receptor signaling during progression to heart failure. METHODS ANDRESULTS:
Based on bioinformatic analysis, ß1-adrenergic receptor (ß1AR) and other components of the ß1AR signal transduction cascade, including adenylate cyclase VI and the catalytic subunit of the cAMP-dependent protein kinase A, were predicted as direct targets of miR-133 and subsequently validated by experimental studies. Consistently, cAMP accumulation and activation of downstream targets were repressed by miR-133 overexpression in both neonatal and adult cardiomyocytes following selective ß1AR stimulation. Furthermore, gain-of-function and loss-of-function studies of miR-133 revealed its role in counteracting the deleterious apoptotic effects caused by chronic ß1AR stimulation. This was confirmed in vivo using a novel cardiac-specific TetON-miR-133 inducible transgenic mouse model. When subjected to transaortic constriction, TetON-miR-133 inducible transgenic mice maintained cardiac performance and showed attenuated apoptosis and reduced fibrosis compared with control mice.CONCLUSIONS:
miR-133 controls multiple components of the ß1AR transduction cascade and is cardioprotective during heart failure.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Second Messenger Systems
/
Receptors, Adrenergic, beta-1
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Cyclic AMP
/
Myocytes, Cardiac
/
MicroRNAs
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Circ Res
Year:
2014
Document type:
Article