A novel miR-371a-5p-mediated pathway, leading to BAG3 upregulation in cardiomyocytes in response to epinephrine, is lost in Takotsubo cardiomyopathy

• Published in: Cell death & disease Vol. 6; no. 10; p. e1948
• Main Authors: d'Avenia, M, Citro, R, De Marco, M, Veronese, A, Rosati, A, Visone, R, Leptidis, S, Philippen, L, Vitale, G, Cavallo, A, Silverio, A, Prota, C, Gravina, P, De Cola, A, Carletti, E, Coppola, G, Gallo, S, Provenza, G, Bossone, E, Piscione, F, Hahne, M, De Windt, L J, Turco, M C, De Laurenzi, V
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2015; Springer Nature B.V; Nature Publishing Group
• Subjects: 14/19; 14/5; 38/23; 42/109; 631/80/86; 692/420; 692/699/75/74; 82; 82/80; 96; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Antibodies; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biochemistry; Biochemistry, Molecular Biology; Biomedical and Life Sciences; Cardiology and cardiovascular system; Cell Biology; Cell Culture; Epinephrine - pharmacology; Female; Human health and pathology; Humans; Immunology; Life Sciences; MicroRNAs - genetics; MicroRNAs - metabolism; MicroRNAs - physiology; Mutation; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Original; original-article; Takotsubo Cardiomyopathy - genetics; Up-Regulation - drug effects
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2015.280

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.