Pharmacological Activation of Nrf2 by Rosolic Acid Attenuates Endoplasmic Reticulum Stress in Endothelial Cells

Abstract

Endoplasmic reticulum (ER) plays a key role in the folding, modification, and trafficking of proteins. When the homeostasis of the ER is disturbed, un/misfolded proteins accumulate in the ER which leads to ER stress. Sustained ER stress results in apoptosis, which is associated with various diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major transcription factor in redox homeostasis by regulating various genes associated with detoxification and cell-protective mechanisms. We found that Rosolic acid (RA) treatment dose-dependently activates Nrf2 in endothelial cells using the enzyme fragment complementation assay. The cytoprotective role of RA against ER stress-induced endothelial apoptosis and its molecular mechanism was explored in the present study. The Nrf2 and its target genes, as well as ER stress marker expressions, were measured by qPCR in ER stress-exposed endothelial cells. The contribution of Nrf2 in RA-mediated defense mechanism in endothelial cells was established by knockout studies using Nrf2-CRISPR/Cas9. The treatment with RA to ER stress-induced endothelial cells exhibited activation of Nrf2, as demonstrated by Nrf2 translocation and reduction of ER stress markers. We found that the Nrf2 knockout sensitized the endothelial cells against ER stress, and further, RA failed to mediate its cytoprotective effect. Proteomic studies using LC-MS/MS revealed that among the 1370 proteins detected, we found 296 differentially regulated proteins in ER stress-induced endothelial cells, and RA administration ameliorated 71 proteins towards the control levels. Of note, the ER stress in endothelial cells was attenuated by the treatment with the RA, suggesting the role of the Nrf2 activator in the pathological conditions of ER stress-associated diseases.

Role of ferroptosis inhibitors in the management of diabetes

“…Another investigation revealed that the antidiabetic drug metformin regulated cellular angiogenesis through the upregulation of Nrf2 levels, causing a reduction in ED in gestational diabetes patients 97 . The evidence from our studies also highlighted that Nrf2 activation could attenuate ED in diabetes through inhibition of ER stress 98,99 . Notably, it was found that Nrf2 played an essential role in maintaining redox homeostasis and angiogenesis in DFU patients, 100 and alterations in the Nrf2 gene was associated with a greater risk of developing DFU 101 .…”

“…97 The evidence from our studies also highlighted that Nrf2 activation could attenuate ED in diabetes through inhibition of ER stress. 98,99 Notably, it was found that Nrf2 played an essential role in maintaining redox homeostasis and angiogenesis in DFU patients, 100 and alterations in the Nrf2 gene was associated with a greater risk of developing DFU. 101 Indeed, it was reported that the aberration of Nrf2 signaling induced by a high glucose microenvironment was associated with diabetic wounds.…”

EETs alleviate alveolar epithelial cell senescence by inhibiting endoplasmic reticulum stress through the Trim25/Keap1/Nrf2 axis

“…In this study, we found that EETs reduced intracellular ROS content and ERS levels in senescent AECs. A large number of studies have shown that the key intracellular anti-oxidant factor Nrf2 and its downstream target gene HO-1 have a significant inhibitory effect on ERS [ 27 , 28 ]. In combination with this study, EETs could promote the protein expression of Nrf2 and HO-1 in AECs.…”

“…Upon oxidative stress, Nrf2 is released from Keap1 and transferred to the nucleus to activate downstream gene expression, including heme oxygenase-1 (HO-1), thus playing an anti-oxidant effect [ 26 ]. Studies have shown that increased expression of Nrf2 inhibits ERS [ 27 , 28 ]. Abnormal Nrf2 signaling has been found in a variety of age-related diseases, including pulmonary fibrosis [ 29 ].…”