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Peserico D, Stranieri C, Garbin U, et al. Ezetimibe Prevents Ischemia/Reperfusion-Induced Oxidative Stress and Up-Regulates Nrf2/ARE and UPR Signaling Pathways. Antioxidants (Basel). 2020;9(4)doi: 10.3390/antiox9040349.
Peserico, D., Stranieri, C., Garbin, U., Mozzini C, C., Danese, E., Cominacini, L., & Fratta Pasini, A. M. (2020). Ezetimibe Prevents Ischemia/Reperfusion-Induced Oxidative Stress and Up-Regulates Nrf2/ARE and UPR Signaling Pathways. Antioxidants (Basel, Switzerland), 9(4), . https://doi.org/10.3390/antiox9040349
Peserico, Denise, et al. "Ezetimibe Prevents Ischemia/Reperfusion-Induced Oxidative Stress and Up-Regulates Nrf2/ARE and UPR Signaling Pathways." Antioxidants (Basel, Switzerland) vol. 9,4 (2020). doi: https://doi.org/10.3390/antiox9040349
Peserico D, Stranieri C, Garbin U, Mozzini C C, Danese E, Cominacini L, Fratta Pasini AM. Ezetimibe Prevents Ischemia/Reperfusion-Induced Oxidative Stress and Up-Regulates Nrf2/ARE and UPR Signaling Pathways. Antioxidants (Basel). 2020 Apr 23;9(4). doi: 10.3390/antiox9040349. PMID: 32340270; PMCID: PMC7222361.
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Antioxidants (Basel). 2020 Apr 23;9(4). doi: 10.3390/antiox9040349.

Ezetimibe Prevents Ischemia/Reperfusion-Induced Oxidative Stress and Up-Regulates Nrf2/ARE and UPR Signaling Pathways.

Antioxidants (Basel, Switzerland)

Denise Peserico, Chiara Stranieri, Ulisse Garbin, Chiara Mozzini C, Elisa Danese, Luciano Cominacini, Anna M Fratta Pasini

Affiliations

  1. Department of Medicine, Section of General Medicine and Atherothrombotic and Degenerative Diseases, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy.
  2. Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy.

PMID: 32340270 PMCID: PMC7222361 DOI: 10.3390/antiox9040349

Abstract

BACKGROUND: While reperfusion is crucial for survival after an episode of ischemia, it also causes oxidative stress. Nuclear factor-E2-related factor 2 (Nrf2) and unfolded protein response (UPR) are protective against oxidative stress and endoplasmic reticulum (ER) stress. Ezetimibe, a cholesterol absorption inhibitor, has been shown to activate the AMP-activated protein kinase (AMPK)/Nrf2 pathway. In this study we evaluated whether Ezetimibe affects oxidative stress and Nrf2 and UPR gene expression in cellular models of ischemia-reperfusion (IR).

METHODS: Cultured cells were subjected to simulated IR with or without Ezetimibe.

RESULTS: IR significantly increased reactive oxygen species (ROS) production and the percentage of apoptotic cells without the up-regulation of Nrf2, of the related antioxidant response element (ARE) gene expression or of the pro-survival UPR activating transcription factor 6 (ATF6) gene, whereas it significantly increased the pro-apoptotic CCAAT-enhancer-binding protein homologous protein (CHOP). Ezetimibe significantly decreased the cellular ROS formation and apoptosis induced by IR. These effects were paralleled by the up-regulation of Nrf2/ARE and ATF6 gene expression and by a down-regulation of CHOP. We also found that Nrf2 activation was dependent on AMPK, since Compound C, a pan inhibitor of p-AMPK, blunted the activation of Nrf2.

CONCLUSIONS: Ezetimibe counteracts IR-induced oxidative stress and induces Nrf2 and UPR pathway activation.

Keywords: ER stress; Ezetimibe; Nrf2; ischemia-reperfusion; oxidative stress

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