Abstract 360: MiR-133 Modulates the Beta1-Adrenergic Receptor Transduction Cascade
Rationale: The sympathetic nervous system plays a fundamental role in the regulation of myocardial function. During chronic pressure overload, over-activation of the sympathetic nervous system induces the release of catecholamines, which activate β-adrenergic receptors (βARs) in cardiomyocytes (CMs) and lead to increased heart rate and cardiac contractility. However, chronic stimulation of βARs leads to impaired cardiac function and β-blockers are widely used as therapeutic agents for the treatment of cardiac disease. MiR-133 is highly expressed in the myocardium and is involved in controlling cardiac function through regulation of mRNA translation/stability.
Objective: To determine whether miR-133 affects βAR signaling during progression to heart failure.
Methods and Results: Based on bioinformatic analysis, 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 (PKA), 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 CMs following selective β1AR stimulation. Furthermore, gain- 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 cardiacspecific TetON-miR-133 inducible transgenic mouse model (Tg133). When subjected to transaortic constriction, Tg133 mice maintained cardiac performance and showed attenuated apoptosis and reduced fibrosis compared to control mice.
Conclusions: MiR-133 controls multiple components of the β1AR transduction cascade and is cardioprotective during heart failure.
Author Disclosures: A. Castaldi: None T. Zaglia: None V. Di Mauro: None P. Carullo: None G. Viggiani: None G. Borile: None B. Di Stefano: None G. Schiattarella: None M. Gualazzi: None L. Elia: None G. Stirparo: None G. Pironti: None P. Kunderfranco: None M. Colorito: None G. Esposito: None M. Bang: None M. Mongillo: None G. Condorelli: None D. Catalucci: None.
- © 2014 by American Heart Association, Inc.