MicroRNA-133 modulates the β1-adrenergic receptor transduction cascade

Alessandra Castaldi, Tania Zaglia, Vittoria Di Mauro, Pierluigi Carullo, Giacomo Viggiani, Giulia Borile, Barbara Di Stefano, Gabriele Giacomo Schiattarella, Maria Giovanna Gualazzi, Leonardo Elia, Giuliano Giuseppe Stirparo, Maria Luisa Colorito, Gianluigi Pironti, Paolo Kunderfranco, Giovanni Esposito, Marie Louise Bang, Marco Mongillo, Gianluigi Condorelli, Daniele Catalucci

Research output: Contribution to journalArticle

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, β1-adrenergic receptor (β1AR) and other components of the β1AR 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 β1AR 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 β1AR 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 β1AR transduction cascade and is cardioprotective during heart failure.

Original languageEnglish
Pages (from-to)273-283
Number of pages11
JournalCirculation Research
Volume115
Issue number2
DOIs
Publication statusPublished - Jul 7 2014

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MicroRNAs
Adrenergic Receptors
Sympathetic Nervous System
Cyclic AMP-Dependent Protein Kinases
Cardiac Myocytes
Transgenic Mice
Heart Failure
RNA Stability
Computational Biology
Adenylyl Cyclases
Constriction
Catecholamines
Heart Diseases
Signal Transduction
Catalytic Domain
Myocardium
Fibrosis
Heart Rate
Apoptosis
Pressure

Keywords

  • adrenergic beta-1 receptor antagonists
  • cardiac
  • cyclic AMP
  • heart failure
  • microRNAs
  • myocytes

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

MicroRNA-133 modulates the β1-adrenergic receptor transduction cascade. / Castaldi, Alessandra; Zaglia, Tania; Di Mauro, Vittoria; Carullo, Pierluigi; Viggiani, Giacomo; Borile, Giulia; Di Stefano, Barbara; Schiattarella, Gabriele Giacomo; Gualazzi, Maria Giovanna; Elia, Leonardo; Stirparo, Giuliano Giuseppe; Colorito, Maria Luisa; Pironti, Gianluigi; Kunderfranco, Paolo; Esposito, Giovanni; Bang, Marie Louise; Mongillo, Marco; Condorelli, Gianluigi; Catalucci, Daniele.

In: Circulation Research, Vol. 115, No. 2, 07.07.2014, p. 273-283.

Research output: Contribution to journalArticle

Castaldi, A, Zaglia, T, Di Mauro, V, Carullo, P, Viggiani, G, Borile, G, Di Stefano, B, Schiattarella, GG, Gualazzi, MG, Elia, L, Stirparo, GG, Colorito, ML, Pironti, G, Kunderfranco, P, Esposito, G, Bang, ML, Mongillo, M, Condorelli, G & Catalucci, D 2014, 'MicroRNA-133 modulates the β1-adrenergic receptor transduction cascade', Circulation Research, vol. 115, no. 2, pp. 273-283. https://doi.org/10.1161/CIRCRESAHA.115.303252
Castaldi, Alessandra ; Zaglia, Tania ; Di Mauro, Vittoria ; Carullo, Pierluigi ; Viggiani, Giacomo ; Borile, Giulia ; Di Stefano, Barbara ; Schiattarella, Gabriele Giacomo ; Gualazzi, Maria Giovanna ; Elia, Leonardo ; Stirparo, Giuliano Giuseppe ; Colorito, Maria Luisa ; Pironti, Gianluigi ; Kunderfranco, Paolo ; Esposito, Giovanni ; Bang, Marie Louise ; Mongillo, Marco ; Condorelli, Gianluigi ; Catalucci, Daniele. / MicroRNA-133 modulates the β1-adrenergic receptor transduction cascade. In: Circulation Research. 2014 ; Vol. 115, No. 2. pp. 273-283.
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AU - Castaldi, Alessandra

AU - Zaglia, Tania

AU - Di Mauro, Vittoria

AU - Carullo, Pierluigi

AU - Viggiani, Giacomo

AU - Borile, Giulia

AU - Di Stefano, Barbara

AU - Schiattarella, Gabriele Giacomo

AU - Gualazzi, Maria Giovanna

AU - Elia, Leonardo

AU - Stirparo, Giuliano Giuseppe

AU - Colorito, Maria Luisa

AU - Pironti, Gianluigi

AU - Kunderfranco, Paolo

AU - Esposito, Giovanni

AU - Bang, Marie Louise

AU - Mongillo, Marco

AU - Condorelli, Gianluigi

AU - Catalucci, Daniele

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N2 - 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, β1-adrenergic receptor (β1AR) and other components of the β1AR 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 β1AR 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 β1AR 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 β1AR transduction cascade and is cardioprotective during heart failure.

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