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Pharmacological activation of Nrf2 by rosolic acid attenuates endoplasmic reticulum stress in endothelial cells
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  • Karan Naresh Amin,
  • Rajaguru Palanisamy,
  • koustav Sarkar,
  • M.R. Ganesh,
  • Takayoshi Suzuki,
  • Ramkumar Kunka mohanram
Karan Naresh Amin
SRM Institute of Science and Technology
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Rajaguru Palanisamy
Anna University of Technology
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koustav Sarkar
SRM Institute of Science and Technology
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M.R. Ganesh
SRM Institute of Science and Technology
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Takayoshi Suzuki
NIHS
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Ramkumar Kunka mohanram
SRM Institute of Science and Technology
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Abstract

Background and Purpose: Endoplasmic reticulum (ER) stress is an underlying mechanism intricate in the pathogenesis of endothelial cell apoptosis and loss of function. Nuclear factor erythroid 2-related factor 2 (Nrf2) acts as a chief transcription regulator of several drug-metabolizing and cytoprotective enzymes. We identified Rosolic acid (RA) as a potent Nrf2 activator using a reporter assay. We explored whether RA can defend endothelial cells against ER stress-induced apoptosis through the activation of Nrf2 and explored its underlying mechanism. Experimental Approach: Nrf2 expression and its downstream regulation along with ER stress markers were assessed by qPCR in Thapsigargin (THP)-induced endothelial cells. The antiapoptotic role of RA was studied using the annexin-V binding assay. The role Nrf2 in RA mediated protection was confirmed by Nrf2 knock out using CRISPR-Cas9 in endothelial cells. Further, its molecular mechanism was studied using a proteomic approach by LC-MS/MS. Key Results: RA treatment showed activation of Nrf2 and suppression of ER stress markers in THP-induced endothelial cells. The suppression of Nrf2 sensitized the cells to ER stress and RA failed to show its cytoprotective effect. Proteomic analysis revealed that among the 1370 proteins detected, 296 proteins were differentially regulated in THP-treated endothelial cells with a two-fold difference (P<0.05), and on RA administration 71 proteins were stabilized towards control levels. Conclusion and Implications: The present study demonstrates the beneficial effect of Nrf2 activation as a promising strategy to defend endothelial cells against ER-stress induced toxicity.