1. MiR-133 Modulates the β1Adrenergic Receptor Transduction Cascade
- Author
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Gabriele G. Schiattarella, Maria Luisa Colorito, Marco Mongillo, Giacomo Viggiani, Giovanni Esposito, Vittoria Di Mauro, Leonardo Elia, Maria Giovanna Gualazzi, Giulia Borile, Paolo Kunderfranco, Marie Louise Bang, Pierluigi Carullo, Barbara Di Stefano, Gianluigi Condorelli, Tania Zaglia, Gianluigi Pironti, Alessandra Castaldi, Giuliano Giuseppe Stirparo, Daniele Catalucci, A., Castaldi, T., Zaglia, V., Di Mauro, P., Carullo, G., Viggiani, G., Borile, B., Di Stefano, G. G., Schiattarella, M. G., Gualazzi, L., Elia, G. G., Stirparo, M. L., Colorito, G., Pironti, P., Kunderfranco, Esposito, Giovanni, M. L., Bang, M., Mongillo, G., Condorelli, and D., Catalucci
- Subjects
Male ,Physiology ,Messenger ,heart failure ,Apoptosis ,cardiomyocytes ,Inbred C57BL ,Second Messenger Systems ,Transgenic ,Rats, Sprague-Dawley ,Beta-1 adrenergic receptor ,Mice ,Genes, Reporter ,Receptors ,Cyclic AMP ,Guanine Nucleotide Exchange Factors ,Myocytes, Cardiac ,Alpha-1D adrenergic receptor ,3' Untranslated Regions ,Cells, Cultured ,Cultured ,biology ,Chemistry ,adrenergic beta-1 receptor antagonists ,cardiac ,cyclic AMP ,microRNAs ,myocytes ,Adenylyl Cyclases ,Animals ,Cyclic AMP-Dependent Protein Kinases ,Disease Progression ,Gene Expression Regulation ,Metoprolol ,Mice, Inbred C57BL ,Mice, Transgenic ,MicroRNAs ,Myocardium ,RNA, Messenger ,Rats ,Receptors, Adrenergic, beta-1 ,Recombinant Fusion Proteins ,Cardiology and Cardiovascular Medicine ,Medicine (all) ,Cell biology ,Adrenergic ,CARDIAC HYPERTROPHY ,Signal transduction ,medicine.medical_specialty ,Adrenergic receptor ,Cells ,beta-1 ,Alpha-1B adrenergic receptor ,Internal medicine ,cAMP ,medicine ,Reporter ,Pressure overload ,alpha and beta adrenoceptors ,Myocytes ,Beta adrenergic receptor kinase ,Alpha-1A adrenergic receptor ,Endocrinology ,Genes ,biology.protein ,RNA ,Sprague-Dawley - 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 1 AR transduction cascade and is cardioprotective during heart failure.
- Published
- 2014