Alessandra Castaldi1, Tania Zaglia1, Vittoria Di Mauro1, Pierluigi Carullo1, Giacomo Viggiani1, Giulia Borile1, Barbara Di Stefano1, Gabriele Giacomo Schiattarella1, Maria Giovanna Gualazzi1, Leonardo Elia1, Giuliano Giuseppe Stirparo1, Maria Luisa Colorito1, Gianluigi Pironti1, Paolo Kunderfranco1, Giovanni Esposito1, Marie-Louise Bang1, Marco Mongillo1, Gianluigi Condorelli1, Daniele Catalucci2. 1. From the Humanitas Clinical and Research Center, Rozzano, Milan, Italy (A.C., V.D.M., P.C., G.V., M.G.G., G.G.S., P.K., M.-L.B., G.C., D.C.); Multimedica, Milan, Italy (L.E.); University of Milan Bicocca, Milan, Italy (A.C.); Venetian Institute of Molecular Medicine, Padova, Italy (T.Z., G.B., M.M.); University of Padova, Padova, Italy (T.Z., G.B., M.M.); Institute of Genetic and Biomedical Research-Milan Unit, Milan, Italy (P.C., M.-L.B., G.C., D.C.); University "Federico II," Naples, Italy (G.G.S., G.E.); University of Milan, Milan, Italy (G.G.S., G.C.); Duke University Medical Center, Durham, NC (G.P.); and University of Palermo, Palermo, Italy (B.D.S., M.L.C.). 2. From the Humanitas Clinical and Research Center, Rozzano, Milan, Italy (A.C., V.D.M., P.C., G.V., M.G.G., G.G.S., P.K., M.-L.B., G.C., D.C.); Multimedica, Milan, Italy (L.E.); University of Milan Bicocca, Milan, Italy (A.C.); Venetian Institute of Molecular Medicine, Padova, Italy (T.Z., G.B., M.M.); University of Padova, Padova, Italy (T.Z., G.B., M.M.); Institute of Genetic and Biomedical Research-Milan Unit, Milan, Italy (P.C., M.-L.B., G.C., D.C.); University "Federico II," Naples, Italy (G.G.S., G.E.); University of Milan, Milan, Italy (G.G.S., G.C.); Duke University Medical Center, Durham, NC (G.P.); and University of Palermo, Palermo, Italy (B.D.S., M.L.C.). daniele.catalucci@cnr.it.
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.
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.
Authors: Shyam Sundar Nandi; Hong Zheng; Neeru M Sharma; Hamid R Shahshahan; Kaushik P Patel; Paras K Mishra Journal: Diabetes Date: 2016-07-13 Impact factor: 9.461
Authors: Neeru M Sharma; Shyam S Nandi; Hong Zheng; Paras K Mishra; Kaushik P Patel Journal: Am J Physiol Heart Circ Physiol Date: 2017-03-10 Impact factor: 4.733