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

F. Carlomosti, M. D'Agostino, S. Beji, A. Torcinaro, R. Rizzi, G. Zaccagnini, B. Maimone, V. Di Stefano, F. De Santa, S. Cordisco, A. Antonini, R. Ciarapica, E. Dellambra, F. Martelli, D. Avitabile, M.C. Capogrossi, A. Magenta

Research output: Contribution to journalArticle

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. © 2017, Mary Ann Liebert, Inc.
Original languageEnglish
Pages (from-to)328-344
Number of pages17
JournalAntioxidants and Redox Signaling
Volume27
Issue number6
DOIs
Publication statusPublished - 2017

Keywords

  • aging
  • Free radicals
  • microRNA
  • nitric oxide
  • vascular
  • catalase
  • endothelial nitric oxide synthase
  • manganese superoxide dismutase
  • microRNA 200c
  • sirtuin 1
  • transcription factor FKHR
  • aged
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • down regulation
  • femoral artery
  • gene targeting
  • human
  • human cell
  • human tissue
  • in vitro study
  • in vivo study
  • limb ischemia
  • limb perfusion
  • male
  • mouse
  • nonhuman
  • oxidative stress
  • priority journal
  • protein acetylation
  • protein interaction
  • protein modification
  • protein phosphorylation
  • regulatory mechanism
  • skin fibroblast
  • transcription regulation
  • upregulation

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    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, M. C., & Magenta, A. (2017). Oxidative Stress-Induced miR-200c Disrupts the Regulatory Loop among SIRT1, FOXO1, and eNOS. Antioxidants and Redox Signaling, 27(6), 328-344. https://doi.org/10.1089/ars.2016.6643