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Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin

OBJECTIVE: Oxidative stress induced by free fatty acids contributes to the development of cardiovascular diseases in patients with metabolic syndrome. Reducing oxidative stress may attenuate these pathogenic processes. Activation of AMP-activated protein kinase (AMPK) has been reported to reduce int...

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Autores principales: Li, Xiao-Nan, Song, Jun, Zhang, Lin, LeMaire, Scott A., Hou, Xiaoyang, Zhang, Cheng, Coselli, Joseph S., Chen, Li, Wang, Xing Li, Zhang, Yun, Shen, Ying H.
Formato: Texto
Lenguaje:English
Publicado: American Diabetes Association 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750236/
https://www.ncbi.nlm.nih.gov/pubmed/19592618
http://dx.doi.org/10.2337/db08-1512
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author Li, Xiao-Nan
Song, Jun
Zhang, Lin
LeMaire, Scott A.
Hou, Xiaoyang
Zhang, Cheng
Coselli, Joseph S.
Chen, Li
Wang, Xing Li
Zhang, Yun
Shen, Ying H.
author_facet Li, Xiao-Nan
Song, Jun
Zhang, Lin
LeMaire, Scott A.
Hou, Xiaoyang
Zhang, Cheng
Coselli, Joseph S.
Chen, Li
Wang, Xing Li
Zhang, Yun
Shen, Ying H.
author_sort Li, Xiao-Nan
collection PubMed
description OBJECTIVE: Oxidative stress induced by free fatty acids contributes to the development of cardiovascular diseases in patients with metabolic syndrome. Reducing oxidative stress may attenuate these pathogenic processes. Activation of AMP-activated protein kinase (AMPK) has been reported to reduce intracellular reactive oxygen species (ROS) levels. The thioredoxin (Trx) system is a major antioxidant system. In this study, we investigated the mechanisms involved in the AMPK-mediated regulation of Trx expression and the reduction of intracellular ROS levels. RESEARCH DESIGN AND METHODS: We observed that activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) significantly reduced ROS levels induced by palmitic acid in human aortic endothelial cells. Activation of AMPK increased expression of the antioxidant Trx, which mediated the ROS reduction. RT-PCR showed that AMPK regulated Trx at the transcriptional level. RESULTS: Forkhead transcription factor 3 (FOXO3) was identified as the target transcription factor involved in the upregulation of Trx expression. FOXO3 bound to the Trx promoter, recruited the histone acetylase p300 to the Trx promoter, and formed a transcription activator complex, which was enhanced by AICAR treatment. AMPK activated FOXO3 by promoting its nuclear translocation. We further showed that AICAR injection increased the expression of Trx and decreased ROS production in the aortic wall of ApoE−/− mice fed a high-fat diet. CONCLUSIONS: These results suggest that activation of the AMPK-FOXO3 pathway reduces ROS levels by inducing Trx expression. Thus, the AMPK-FOXO3-Trx axis may be an important defense mechanism against excessive ROS production induced by metabolic stress and could be a therapeutic target in treating cardiovascular diseases in metabolic syndrome.
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spelling pubmed-27502362010-10-01 Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin Li, Xiao-Nan Song, Jun Zhang, Lin LeMaire, Scott A. Hou, Xiaoyang Zhang, Cheng Coselli, Joseph S. Chen, Li Wang, Xing Li Zhang, Yun Shen, Ying H. Diabetes Original Article OBJECTIVE: Oxidative stress induced by free fatty acids contributes to the development of cardiovascular diseases in patients with metabolic syndrome. Reducing oxidative stress may attenuate these pathogenic processes. Activation of AMP-activated protein kinase (AMPK) has been reported to reduce intracellular reactive oxygen species (ROS) levels. The thioredoxin (Trx) system is a major antioxidant system. In this study, we investigated the mechanisms involved in the AMPK-mediated regulation of Trx expression and the reduction of intracellular ROS levels. RESEARCH DESIGN AND METHODS: We observed that activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) significantly reduced ROS levels induced by palmitic acid in human aortic endothelial cells. Activation of AMPK increased expression of the antioxidant Trx, which mediated the ROS reduction. RT-PCR showed that AMPK regulated Trx at the transcriptional level. RESULTS: Forkhead transcription factor 3 (FOXO3) was identified as the target transcription factor involved in the upregulation of Trx expression. FOXO3 bound to the Trx promoter, recruited the histone acetylase p300 to the Trx promoter, and formed a transcription activator complex, which was enhanced by AICAR treatment. AMPK activated FOXO3 by promoting its nuclear translocation. We further showed that AICAR injection increased the expression of Trx and decreased ROS production in the aortic wall of ApoE−/− mice fed a high-fat diet. CONCLUSIONS: These results suggest that activation of the AMPK-FOXO3 pathway reduces ROS levels by inducing Trx expression. Thus, the AMPK-FOXO3-Trx axis may be an important defense mechanism against excessive ROS production induced by metabolic stress and could be a therapeutic target in treating cardiovascular diseases in metabolic syndrome. American Diabetes Association 2009-10 2009-07-10 /pmc/articles/PMC2750236/ /pubmed/19592618 http://dx.doi.org/10.2337/db08-1512 Text en © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Original Article
Li, Xiao-Nan
Song, Jun
Zhang, Lin
LeMaire, Scott A.
Hou, Xiaoyang
Zhang, Cheng
Coselli, Joseph S.
Chen, Li
Wang, Xing Li
Zhang, Yun
Shen, Ying H.
Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin
title Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin
title_full Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin
title_fullStr Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin
title_full_unstemmed Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin
title_short Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin
title_sort activation of the ampk-foxo3 pathway reduces fatty acid–induced increase in intracellular reactive oxygen species by upregulating thioredoxin
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750236/
https://www.ncbi.nlm.nih.gov/pubmed/19592618
http://dx.doi.org/10.2337/db08-1512
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