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A dual Keap1 and p47(phox) inhibitor Ginsenoside Rb1 ameliorates high glucose/ox-LDL-induced endothelial cell injury and atherosclerosis

Oxidative stress is a vital contributor to the development and progression of diabetes-accelerated atherosclerosis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known molecule that participates in cellular defense against oxidative stress. Utilizing luciferase reporter assay from 379...

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Autores principales: Wang, Zi-Chao, Niu, Kai-Ming, Wu, Yu-Jie, Du, Kai-Rui, Qi, Lian-Wen, Zhou, Ye-Bo, Sun, Hai-Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9512801/
https://www.ncbi.nlm.nih.gov/pubmed/36163178
http://dx.doi.org/10.1038/s41419-022-05274-x
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author Wang, Zi-Chao
Niu, Kai-Ming
Wu, Yu-Jie
Du, Kai-Rui
Qi, Lian-Wen
Zhou, Ye-Bo
Sun, Hai-Jian
author_facet Wang, Zi-Chao
Niu, Kai-Ming
Wu, Yu-Jie
Du, Kai-Rui
Qi, Lian-Wen
Zhou, Ye-Bo
Sun, Hai-Jian
author_sort Wang, Zi-Chao
collection PubMed
description Oxidative stress is a vital contributor to the development and progression of diabetes-accelerated atherosclerosis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known molecule that participates in cellular defense against oxidative stress. Utilizing luciferase reporter assay from 379 natural products, we reported here that Ginsenoside Rb1 played a dual role in inhibiting Kelch-like ECH-associated protein 1 (Keap1) and p47(phox) luciferase reporter activities. In endothelial cells (ECs), Rb1 pretreatment enhanced cell viability, reduced oxidative stress, inflammation, endothelial-mesenchymal transition (EndMT), and apoptosis, as well as ameliorated mitochondrial quality following oxidized low-density lipoprotein (ox-LDL) plus high glucose (HG) challenge. Rb1 directly bound to Keap1 and promoted its ubiquitination and proteasomal degradation dependent on lysine residues (K108, K323, and K551) by recruiting the E3 ligase synovial apoptosis inhibitor 1 (SYVN1), leading to Nrf2 dissociation from Keap1, Nrf2 nuclear translocation, Nrf2/PGC-1α complex formation. We further identified that Rb1 could bind to p47(phox) and reduce its phosphorylation and membrane translocation, thereby disrupting the assembly of the NOX2 complex. Importantly, Rb1-mediated preservation of cytoplasmic p47(phox) stabilized and contributed to Nrf2 activation. Additionally, we revealed that Rb1 reduced aortic atherosclerotic plaque formation along with reductions in oxidative stress and inflammatory response in streptozotocin (STZ)-induced ApoE(−/−) mice, but not in ApoE(−/−) mice with deficiency of Nrf2 and PGC-1α. Collectively, we demonstrated that Rb1, which directly targeted Keap1 and p47(phox) in ECs, may be an attractive candidate for the treatment of atherosclerosis in diabetes.
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spelling pubmed-95128012022-09-28 A dual Keap1 and p47(phox) inhibitor Ginsenoside Rb1 ameliorates high glucose/ox-LDL-induced endothelial cell injury and atherosclerosis Wang, Zi-Chao Niu, Kai-Ming Wu, Yu-Jie Du, Kai-Rui Qi, Lian-Wen Zhou, Ye-Bo Sun, Hai-Jian Cell Death Dis Article Oxidative stress is a vital contributor to the development and progression of diabetes-accelerated atherosclerosis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known molecule that participates in cellular defense against oxidative stress. Utilizing luciferase reporter assay from 379 natural products, we reported here that Ginsenoside Rb1 played a dual role in inhibiting Kelch-like ECH-associated protein 1 (Keap1) and p47(phox) luciferase reporter activities. In endothelial cells (ECs), Rb1 pretreatment enhanced cell viability, reduced oxidative stress, inflammation, endothelial-mesenchymal transition (EndMT), and apoptosis, as well as ameliorated mitochondrial quality following oxidized low-density lipoprotein (ox-LDL) plus high glucose (HG) challenge. Rb1 directly bound to Keap1 and promoted its ubiquitination and proteasomal degradation dependent on lysine residues (K108, K323, and K551) by recruiting the E3 ligase synovial apoptosis inhibitor 1 (SYVN1), leading to Nrf2 dissociation from Keap1, Nrf2 nuclear translocation, Nrf2/PGC-1α complex formation. We further identified that Rb1 could bind to p47(phox) and reduce its phosphorylation and membrane translocation, thereby disrupting the assembly of the NOX2 complex. Importantly, Rb1-mediated preservation of cytoplasmic p47(phox) stabilized and contributed to Nrf2 activation. Additionally, we revealed that Rb1 reduced aortic atherosclerotic plaque formation along with reductions in oxidative stress and inflammatory response in streptozotocin (STZ)-induced ApoE(−/−) mice, but not in ApoE(−/−) mice with deficiency of Nrf2 and PGC-1α. Collectively, we demonstrated that Rb1, which directly targeted Keap1 and p47(phox) in ECs, may be an attractive candidate for the treatment of atherosclerosis in diabetes. Nature Publishing Group UK 2022-09-26 /pmc/articles/PMC9512801/ /pubmed/36163178 http://dx.doi.org/10.1038/s41419-022-05274-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wang, Zi-Chao
Niu, Kai-Ming
Wu, Yu-Jie
Du, Kai-Rui
Qi, Lian-Wen
Zhou, Ye-Bo
Sun, Hai-Jian
A dual Keap1 and p47(phox) inhibitor Ginsenoside Rb1 ameliorates high glucose/ox-LDL-induced endothelial cell injury and atherosclerosis
title A dual Keap1 and p47(phox) inhibitor Ginsenoside Rb1 ameliorates high glucose/ox-LDL-induced endothelial cell injury and atherosclerosis
title_full A dual Keap1 and p47(phox) inhibitor Ginsenoside Rb1 ameliorates high glucose/ox-LDL-induced endothelial cell injury and atherosclerosis
title_fullStr A dual Keap1 and p47(phox) inhibitor Ginsenoside Rb1 ameliorates high glucose/ox-LDL-induced endothelial cell injury and atherosclerosis
title_full_unstemmed A dual Keap1 and p47(phox) inhibitor Ginsenoside Rb1 ameliorates high glucose/ox-LDL-induced endothelial cell injury and atherosclerosis
title_short A dual Keap1 and p47(phox) inhibitor Ginsenoside Rb1 ameliorates high glucose/ox-LDL-induced endothelial cell injury and atherosclerosis
title_sort dual keap1 and p47(phox) inhibitor ginsenoside rb1 ameliorates high glucose/ox-ldl-induced endothelial cell injury and atherosclerosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9512801/
https://www.ncbi.nlm.nih.gov/pubmed/36163178
http://dx.doi.org/10.1038/s41419-022-05274-x
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