title: A novel miR-371a-5p-mediated pathway, leading to BAG3 upregulation in cardiomyocytes in response to epinephrine, is lost in Takotsubo cardiomyopathy.
abstract: Molecular mechanisms protecting cardiomyocytes from stress-induced death, including tension stress, are essential for cardiac physiology and defects in these protective mechanisms can result in pathological alterations. Bcl2-associated athanogene 3 (BAG3) is expressed in cardiomyocytes and is a component of the chaperone-assisted autophagy pathway, essential for homeostasis of mechanically altered cells. BAG3 ablation in mice results in a lethal cardiomyopathy soon after birth and mutations of this gene have been associated with different cardiomyopathies including stress-induced Takotsubo cardiomyopathy (TTC). The pathogenic mechanism leading to TTC has not been defined, but it has been suggested that the heart can be damaged by excessive epinephrine (epi) spillover in the absence of a protective mechanism. The aim of this study was to provide more evidence for a role of BAG3 in the pathogenesis of TTC. Therefore, we sequenced BAG3 gene in 70 TTC patients and in 81 healthy donors with the absence of evaluable cardiovascular disease. Mutations and polymorphisms detected in the BAG3 gene included a frequent nucleotide change g2252c in the BAG3 3'-untranslated region (3'-UTR) of Takotsubo patients (P<0.05), resulting in loss of binding of microRNA-371a-5p (miR-371a-5p) as evidenced by dual-luciferase reporter assays and argonaute RNA-induced silencing complex catalytic component 2/pull-down assays. Moreover, we describe a novel signaling pathway in cardiomyocytes that leads to BAG3 upregulation on exposure to epi through an ERK-dependent upregulation of miR-371a-5p. In conclusion, the presence of a g2252c polymorphism in the BAG3 3'-UTR determines loss of miR-371a-5p binding and results in an altered response to epi, potentially representing a new molecular mechanism that contributes to TTC pathogenesis.
authors.affiliation: Department of Pharmacy (DIFARMA), University of Salerno, Fisciano, Italy.|Biouniversa s.r.l., c/o University of Salerno, Fisciano, Italy.|Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy.
authors.forename: M
authors.initials: M
authors.lastname: d'Avenia
authors.affiliation: 'Cuore' Department, University Hospital 'San Giovanni di Dio e Ruggi d'Aragona', Salerno, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Citro
authors.affiliation: Department of Pharmacy (DIFARMA), University of Salerno, Fisciano, Italy.|Biouniversa s.r.l., c/o University of Salerno, Fisciano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: De Marco
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, CeSI, Universita' 'G. D'Annunzio' di Chieti e Pescara, Pescara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Veronese
authors.affiliation: Department of Pharmacy (DIFARMA), University of Salerno, Fisciano, Italy.|Biouniversa s.r.l., c/o University of Salerno, Fisciano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Rosati
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, CeSI, Universita' 'G. D'Annunzio' di Chieti e Pescara, Pescara, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Visone
authors.affiliation: Faculty of Health, Medicine and Life Sciences, Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Leptidis
authors.affiliation: Faculty of Health, Medicine and Life Sciences, Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Philippen
authors.affiliation: 'Cuore' Department, University Hospital 'San Giovanni di Dio e Ruggi d'Aragona', Salerno, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Vitale
authors.affiliation: 'Cuore' Department, University Hospital 'San Giovanni di Dio e Ruggi d'Aragona', Salerno, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cavallo
authors.affiliation: 'Cuore' Department, University Hospital 'San Giovanni di Dio e Ruggi d'Aragona', Salerno, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Silverio
authors.affiliation: 'Cuore' Department, University Hospital 'San Giovanni di Dio e Ruggi d'Aragona', Salerno, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Prota
authors.affiliation: Department of Laboratory Medicine, 'Tor Vergata' University, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Gravina
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, CeSI, Universita' 'G. D'Annunzio' di Chieti e Pescara, Pescara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: De Cola
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, CeSI, Universita' 'G. D'Annunzio' di Chieti e Pescara, Pescara, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Carletti
authors.affiliation: Transfusional Department, University Hospital 'San Giovanni di Dio e Ruggi d'Aragona', Salerno, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Transfusional Department, University Hospital 'San Giovanni di Dio e Ruggi d'Aragona', Salerno, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Gallo
authors.affiliation: Division of Cardiology San Francesco d'Assisi, Hospital of Oliveto Citra, Salerno, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Provenza
authors.affiliation: 'Cuore' Department, University Hospital 'San Giovanni di Dio e Ruggi d'Aragona', Salerno, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Bossone
authors.affiliation: 'Cuore' Department, University Hospital 'San Giovanni di Dio e Ruggi d'Aragona', Salerno, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Piscione
authors.affiliation: Institut de Genetique Moleculaire de Montpellier, CNRS UMR5535, Montpellier, France.
authors.forename: M
authors.initials: M
authors.lastname: Hahne
authors.affiliation: Faculty of Health, Medicine and Life Sciences, Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
authors.forename: L J
authors.initials: LJ
authors.lastname: De Windt
authors.affiliation: Biouniversa s.r.l., c/o University of Salerno, Fisciano, Italy.|Department of Medicine and Surgery, University of Salerno, Fisciano, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Turco
authors.affiliation: Biouniversa s.r.l., c/o University of Salerno, Fisciano, Italy.|Dipartimento di Scienze Mediche, Orali e Biotecnologiche, CeSI, Universita' 'G. D'Annunzio' di Chieti e Pescara, Pescara, Italy.
authors.forename: V
authors.initials: V
authors.lastname: De Laurenzi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology*; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D054549:Takotsubo Cardiomyopathy / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C554834:MIRN371 microRNA, human; D035683:MicroRNAs; D004837:Epinephrine