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

Item Type:Article
Title:MicroRNA-133 modulates the β(1)-adrenergic receptor transduction cascade
Creators Name:Castaldi, A. and Zaglia, T. and Di Mauro, V. and Carullo, P. and Viggiani, G. and Borile, G. and Di Stefano, B. and Schiattarella, G.G. and Gualazzi, M.G. and Elia, L. and Stirparo, G.G. and Colorito, M.L. and Pironti, G. and Kunderfranco, P. and Esposito, G. and Bang, M.L. and Mongillo, M. and 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
Publisher:American Heart Association
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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