| First Author | Castaldi A | Year | 2014 |
| Journal | Circ Res | Volume | 115 |
| Issue | 2 | Pages | 273-83 |
| PubMed ID | 24807785 | Mgi Jnum | J:246232 |
| Mgi Id | MGI:5920736 | Doi | 10.1161/CIRCRESAHA.115.303252 |
| Citation | Castaldi A, et al. (2014) MicroRNA-133 modulates the beta1-adrenergic receptor transduction cascade. Circ Res 115(2):273-83 |
| abstractText | 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 beta-adrenergic receptors in cardiomyocytes and lead to increased heart rate and cardiac contractility. However, chronic stimulation of beta-adrenergic receptors leads to impaired cardiac function, and beta-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 beta-adrenergic receptor signaling during progression to heart failure. METHODS AND RESULTS: Based on bioinformatic analysis, beta1-adrenergic receptor (beta1AR) and other components of the beta1AR 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 beta1AR 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 beta1AR 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 beta1AR transduction cascade and is cardioprotective during heart failure. |
