Oxidative Stress-Induced miR-200c Disrupts the Regulatory Loop among SIRT1, FOXO1, and eNOS

Fabrizio Carlomosti, Marco D'Agostino, Sara Beji, Alessio Torcinaro, Roberto Rizzi, Germana Zaccagnini, Biagina Maimone, Valeria Di Stefano, Francesca De Santa, Sonia Cordisco, Annalisa Antonini, Roberta Ciarapica, Elena Dellambra, Fabio Martelli, Daniele Avitabile, Maurizio Colognesi Capogrossi, Alessandra Magenta

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Aims: Reactive oxygen species (ROS) play a pivotal role in different pathologic conditions, including ischemia, diabetes, and aging. We previously showed that ROS enhance miR-200c expression, causing endothelial cell (EC) apoptosis and senescence. Herein, we dissect the interaction among miR-200c and three strictly related proteins that modulate EC function and ROS production: sirtuin 1 (SIRT1), endothelial nitric oxide synthase (eNOS), and forkhead box O1 (FOXO1). Moreover, the role of miR-200c on ROS modulation was also investigated. Results: We demonstrated that miR-200c directly targets SIRT1, eNOS, and FOXO1; via this mechanism, miR-200c decreased NO and increased the acetylation of SIRT1 targets, that is, FOXO1 and p53. FOXO1 acetylation inhibited its transcriptional activity on target genes, that is, SIRT1 and the ROS scavengers, catalase and manganese superoxide dismutase. In keeping, miR-200c increased ROS production and induced p66Shc protein phosphorylation in Ser-36; this mechanism upregulated ROS and inhibited FOXO1 transcription, reinforcing this molecular circuitry. These in vitro results were validated in three in vivo models of oxidative stress, that is, human skin fibroblasts from old donors, femoral arteries from old mice, and a murine model of hindlimb ischemia. In all cases, miR-200c was higher versus control and its targets, that is, SIRT1, eNOS, and FOXO1, were downmodulated. In the mouse hindlimb ischemia model, anti-miR-200c treatment rescued these targets and improved limb perfusion. Innovation and Conclusion: miR-200c disrupts SIRT1/FOXO1/eNOS regulatory loop. This event promotes ROS production and decreases NO, contributing to endothelial dysfunction under conditions of increased oxidative stress such as aging and ischemia.

Original languageEnglish
Pages (from-to)328-344
Number of pages17
JournalAntioxidants and Redox Signaling
Volume27
Issue number6
DOIs
Publication statusPublished - Aug 20 2017

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Sirtuin 1
Oxidative stress
Nitric Oxide Synthase Type III
Reactive Oxygen Species
Oxidative Stress
Ischemia
Acetylation
Endothelial cells
Hindlimb
Endothelial Cells
Aging of materials
Phosphorylation
Cell Aging
Femoral Artery
Transcription
Fibroblasts
Medical problems
Catalase
Superoxide Dismutase
Skin

Keywords

  • aging
  • Free radicals
  • microRNA
  • nitric oxide
  • vascular

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Oxidative Stress-Induced miR-200c Disrupts the Regulatory Loop among SIRT1, FOXO1, and eNOS. / Carlomosti, Fabrizio; D'Agostino, Marco; Beji, Sara; Torcinaro, Alessio; Rizzi, Roberto; Zaccagnini, Germana; Maimone, Biagina; Di Stefano, Valeria; De Santa, Francesca; Cordisco, Sonia; Antonini, Annalisa; Ciarapica, Roberta; Dellambra, Elena; Martelli, Fabio; Avitabile, Daniele; Capogrossi, Maurizio Colognesi; Magenta, Alessandra.

In: Antioxidants and Redox Signaling, Vol. 27, No. 6, 20.08.2017, p. 328-344.

Research output: Contribution to journalArticle

Carlomosti, F, D'Agostino, M, Beji, S, Torcinaro, A, Rizzi, R, Zaccagnini, G, Maimone, B, Di Stefano, V, De Santa, F, Cordisco, S, Antonini, A, Ciarapica, R, Dellambra, E, Martelli, F, Avitabile, D, Capogrossi, MC & Magenta, A 2017, 'Oxidative Stress-Induced miR-200c Disrupts the Regulatory Loop among SIRT1, FOXO1, and eNOS', Antioxidants and Redox Signaling, vol. 27, no. 6, pp. 328-344. https://doi.org/10.1089/ars.2016.6643
Carlomosti, Fabrizio ; D'Agostino, Marco ; Beji, Sara ; Torcinaro, Alessio ; Rizzi, Roberto ; Zaccagnini, Germana ; Maimone, Biagina ; Di Stefano, Valeria ; De Santa, Francesca ; Cordisco, Sonia ; Antonini, Annalisa ; Ciarapica, Roberta ; Dellambra, Elena ; Martelli, Fabio ; Avitabile, Daniele ; Capogrossi, Maurizio Colognesi ; Magenta, Alessandra. / Oxidative Stress-Induced miR-200c Disrupts the Regulatory Loop among SIRT1, FOXO1, and eNOS. In: Antioxidants and Redox Signaling. 2017 ; Vol. 27, No. 6. pp. 328-344.
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AU - Carlomosti, Fabrizio

AU - D'Agostino, Marco

AU - Beji, Sara

AU - Torcinaro, Alessio

AU - Rizzi, Roberto

AU - Zaccagnini, Germana

AU - Maimone, Biagina

AU - Di Stefano, Valeria

AU - De Santa, Francesca

AU - Cordisco, Sonia

AU - Antonini, Annalisa

AU - Ciarapica, Roberta

AU - Dellambra, Elena

AU - Martelli, Fabio

AU - Avitabile, Daniele

AU - Capogrossi, Maurizio Colognesi

AU - Magenta, Alessandra

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N2 - Aims: Reactive oxygen species (ROS) play a pivotal role in different pathologic conditions, including ischemia, diabetes, and aging. We previously showed that ROS enhance miR-200c expression, causing endothelial cell (EC) apoptosis and senescence. Herein, we dissect the interaction among miR-200c and three strictly related proteins that modulate EC function and ROS production: sirtuin 1 (SIRT1), endothelial nitric oxide synthase (eNOS), and forkhead box O1 (FOXO1). Moreover, the role of miR-200c on ROS modulation was also investigated. Results: We demonstrated that miR-200c directly targets SIRT1, eNOS, and FOXO1; via this mechanism, miR-200c decreased NO and increased the acetylation of SIRT1 targets, that is, FOXO1 and p53. FOXO1 acetylation inhibited its transcriptional activity on target genes, that is, SIRT1 and the ROS scavengers, catalase and manganese superoxide dismutase. In keeping, miR-200c increased ROS production and induced p66Shc protein phosphorylation in Ser-36; this mechanism upregulated ROS and inhibited FOXO1 transcription, reinforcing this molecular circuitry. These in vitro results were validated in three in vivo models of oxidative stress, that is, human skin fibroblasts from old donors, femoral arteries from old mice, and a murine model of hindlimb ischemia. In all cases, miR-200c was higher versus control and its targets, that is, SIRT1, eNOS, and FOXO1, were downmodulated. In the mouse hindlimb ischemia model, anti-miR-200c treatment rescued these targets and improved limb perfusion. Innovation and Conclusion: miR-200c disrupts SIRT1/FOXO1/eNOS regulatory loop. This event promotes ROS production and decreases NO, contributing to endothelial dysfunction under conditions of increased oxidative stress such as aging and ischemia.

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KW - aging

KW - Free radicals

KW - microRNA

KW - nitric oxide

KW - vascular

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