title: SIRT1 protects cardiac cells against apoptosis induced by zearalenone or its metabolites α- and β-zearalenol through an autophagy-dependent pathway.
abstract: Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin produced by several species of Fusarium in cereals and agricultural products. The major ZEN metabolites are α-zearalenol (α-ZOL) and β-zearalenol (β-ZOL). In the present study, we investigated the underlying mechanism of the toxicity induced by ZEN, α-ZOL and β-ZOL in cardiac cells (H9c2). We show that treatment with ZEN or its metabolites induces the activation of the mitochondrial pathway of apoptosis as characterized by an increase in ROS generation, a loss of mitochondrial transmembrane potential (ΔΨm) and an activation of caspases. Besides, we demonstrate that these mycotoxins promote the activation of autophagy before the onset of apoptosis. Indeed, we observed that a short-time (6h) treatment with ZEN, α-ZOL or β-ZOL, increased the level of Beclin-1 and LC3-II and induced the accumulation of the CytoID® autophagy detection probe. Moreover, the inhibition of autophagy by Chloroquine significantly increased cell death induced by ZEN, α-ZOL or β-ZOL, suggesting that the activation of autophagy serves as a cardioprotective mechanism against these mycotoxins. In addition, we found that the inhibition (EX527) or the knockdown of SIRT1 (siRNA) significantly increased apoptosis induced by ZEN or its derivatives, whereas SIRT1 activation with RSV greatly prevents the cytotoxic effects of these mycotoxins. By contrast, when autophagy was inhibited by CQ, the activation of SIRT1 by RSV had no protection against the cardiotoxicity of ZEN or its metabolites, suggesting that SIRT1 protects cardiac cells by an autophagy-dependent pathway.
authors.affiliation: Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, 5019 Monastir, Tunisia; Faculty of Sciences of Bizerte, Carthage University, Tunisia.
authors.forename: Intidhar
authors.initials: I
authors.lastname: Ben Salem
authors.affiliation: Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, 5019 Monastir, Tunisia; Faculty of Sciences of Bizerte, Carthage University, Tunisia.
authors.forename: Manel
authors.initials: M
authors.lastname: Boussabbeh
authors.affiliation: Inserm UMR-S 1180, Univ Paris-Sud, Université Paris Saclay, 92296 Chatenay-Malabry, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Pires Da Silva
authors.affiliation: Inserm UMR-S 1180, Univ Paris-Sud, Université Paris Saclay, 92296 Chatenay-Malabry, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Guilbert
authors.affiliation: Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, 5019 Monastir, Tunisia.
authors.forename: Hassen
authors.initials: H
authors.lastname: Bacha
authors.affiliation: Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, 5019 Monastir, Tunisia. Electronic address: salwaabid@yahoo.fr.
authors.forename: Salwa
authors.initials: S
authors.lastname: Abid-Essefi
authors.affiliation: Université Versailles St-Quentin, Inserm UMR-S 1180, Univ Paris-Sud, Université Paris Saclay, 92296 Chatenay-Malabry, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lemaire
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects*; D016923:Cell Death; D002460:Cell Line; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000502:physiology*; D015025:Zearalenone / Q000633:toxicity*; D015029:Zeranol / Q000031:analogs & derivatives* / Q000633:toxicity
chemical_list: D017382:Reactive Oxygen Species; C029659:zearalenol; D015025:Zearalenone; D015029:Zeranol; C488368:Sirt1 protein, rat; D056564:Sirtuin 1
keywords: Apoptosis; Autophagy; SIRT1; ZEN; α-ZOL; β-ZOL