MicroRNA-133 modulates the β(1)-adrenergic receptor transduction cascade

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Item Type:	Article
Title:	MicroRNA-133 modulates the β(1)-adrenergic receptor transduction cascade
Creators Name:	Castaldi, A., Zaglia, T., Di Mauro, V., Carullo, P., Viggiani, G., Borile, G., Di Stefano, B., Schiattarella, G.G., Gualazzi, M.G., Elia, L., Stirparo, G.G., Colorito, M.L., Pironti, G., Kunderfranco, P., Esposito, G., Bang, M.L., Mongillo, M., Condorelli, G. and Catalucci, D.
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 β-adrenergic receptors in cardiomyocytes and lead to increased heart rate and cardiac contractility. However, chronic stimulation of β-adrenergic receptors leads to impaired cardiac function, and β-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 β-adrenergic receptor signaling during progression to heart failure. METHODS AND RESULTS: Based on bioinformatic analysis, β(1)-adrenergic receptor (β(1)AR) and other components of the β(1)AR 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 β(1)AR 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 β(1)AR 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 β(19AR transduction cascade and is cardioprotective during heart failure.)
Keywords:	Adrenergic beta-1 Receptor Antagonists, Cyclic AMP, Heart Failure, MicroRNAs, Cardiac Myocytes, Animals, Mice, Rats
Source:	Circulation Research
ISSN:	0009-7330
Publisher:	American Heart Association
Volume:	115
Number:	2
Page Range:	273-283
Date:	7 July 2014
Official Publication:	https://doi.org/10.1161/CIRCRESAHA.115.303252
PubMed:	View item in PubMed

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