title: MicroRNA-133 modulates the β1-adrenergic receptor transduction cascade.
abstract: BACKGROUND
  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.
  
  
  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.affiliation: 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.).
authors.forename: Alessandra
authors.initials: A
authors.lastname: Castaldi
authors.affiliation: 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.).
authors.forename: Tania
authors.initials: T
authors.lastname: Zaglia
authors.affiliation: 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.).
authors.forename: Vittoria
authors.initials: V
authors.lastname: Di Mauro
authors.affiliation: 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.).
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Carullo
authors.affiliation: 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.).
authors.forename: Giacomo
authors.initials: G
authors.lastname: Viggiani
authors.affiliation: 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.).
authors.forename: Giulia
authors.initials: G
authors.lastname: Borile
authors.affiliation: 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.).
authors.forename: Barbara
authors.initials: B
authors.lastname: Di Stefano
authors.affiliation: 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.).
authors.forename: Gabriele Giacomo
authors.initials: GG
authors.lastname: Schiattarella
authors.affiliation: 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.).
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Gualazzi
authors.affiliation: 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.).
authors.forename: Leonardo
authors.initials: L
authors.lastname: Elia
authors.affiliation: 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.).
authors.forename: Giuliano Giuseppe
authors.initials: GG
authors.lastname: Stirparo
authors.affiliation: 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.).
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Colorito
authors.affiliation: 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.).
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Pironti
authors.affiliation: 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.).
authors.forename: Paolo
authors.initials: P
authors.lastname: Kunderfranco
authors.affiliation: 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.).
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.affiliation: 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.).
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Bang
authors.affiliation: 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.).
authors.forename: Marco
authors.initials: M
authors.lastname: Mongillo
authors.affiliation: 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.).
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.affiliation: 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.
authors.forename: Daniele
authors.initials: D
authors.lastname: Catalucci
mesh_terms: D020413:3' Untranslated Regions / Q000502:physiology; D000262:Adenylyl Cyclases / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology; D008297:Male; D008790:Metoprolol / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015290:Second Messenger Systems / Q000502:physiology*
chemical_list: D020413:3' Untranslated Regions; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D035683:MicroRNAs; C517732:Mirn133 microRNA, mouse; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D011993:Recombinant Fusion Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; D008790:Metoprolol
keywords: adrenergic beta-1 receptor antagonists; cyclic AMP; heart failure; microRNAs; myocytes, cardiac