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Sestrin2 suppression aggravates oxidative stress and apoptosis in endothelial cells subjected to pharmacologically induced endoplasmic reticulum stress

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journal contribution
submitted on 2023-10-29, 10:11 and posted on 2023-10-29, 11:40 authored by Munazza T. Fatima, Maram Hasan, Shahenda S. Abdelsalam, Siveen K. Sivaraman, Heba El-Gamal, Muhammad A. Zahid, Mohamed A. Elrayess, Hesham M. Korashy, Asad Zeidan, Aijaz S. Parray, Abdelali Agouni

Endoplasmic reticulum (ER) stress is an inflammatory response that contributes to endothelial cell dysfunction, a hallmark of cardiovascular diseases, in close interplay with oxidative stress. Recently, Sestrin2 (SESN2) emerged as a novel stress-inducible protein protecting cells from oxidative stress. We investigated here, for the first time, the impact of SESN2 suppression on oxidative stress and cell survival in human endothelial cells subjected to pharmacologically (thapsigargin)-induced ER stress and studied the underlying cellular pathways. We found that SESN2 silencing, though did not specifically induce ER stress, it aggravated the effects of thapsigargin-induced ER stress on oxidative stress and cell survival. This was associated with a dysregulation of Nrf-2, AMPK and mTORC1 signaling pathways. Furthermore, SESN2 silencing aggravated, in an additive manner, apoptosis caused by thapsigargin. Importantly, SESN2 silencing, unlike thapsigargin, caused a dramatic decrease in protein expression and phosphorylation of Akt, a critical pro-survival hub and component of the AMPK/Akt/mTORC1 axis. Our findings suggest that patients with conditions characterized by ER stress activation, such as diabetes, may be at higher risk for cardiovascular complications if their endogenous ability to stimulate and/or maintain expression levels of SESN2 is disturbed or impaired. Therefore, identifying novel or repurposing existing pharmacotherapies to enhance and/or maintain SESN2 expression levels would be beneficial in these conditions.

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Published in: European Journal of Pharmacology
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Open Access funding provided by the Qatar National Library



  • English



Publication Year

  • 2021

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License

Institution affiliated with

  • Qatar University
  • Biomedical Research Center - QU
  • Qatar University Health - QU
  • College of Pharmacy - QU HEALTH
  • College of Medicine - QU HEALTH
  • Biomedical and Pharmaceutical Research Unit - QU HEALTH
  • Hamad Medical Corporation
  • Academic Health System - HMC
  • Neurosciences Institute - HMC
  • Interim Translational Research Institute - HMC