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Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin
Diabetes (New York, N.Y.), 2009-10, Vol.58 (10), p.2246-2257
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
2009
Details
Autor(en) / Beteiligte
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
Titel
Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin
Ist Teil von
Diabetes (New York, N.Y.), 2009-10, Vol.58 (10), p.2246-2257
Ort / Verlag
United States: American Diabetes Association
Erscheinungsjahr
2009
Link zum Volltext
Quelle
Electronic Journals Library
Beschreibungen/Notizen
Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin Xiao-Nan Li 1 , 2 , 3 , Jun Song 1 , 2 , 3 , Lin Zhang 1 , 2 , Scott A. LeMaire 1 , 2 , Xiaoyang Hou 1 , 2 , 3 , Cheng Zhang 1 , 2 , 3 , Joseph S. Coselli 1 , 2 , Li Chen 3 , Xing Li Wang 1 , 2 , Yun Zhang 3 and Ying H. Shen 1 , 2 1 Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas; 2 Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, Texas; 3 Qilu Hospital, Shandong University, Jinan, Shandong, China. Corresponding authors: Yun Zhang, zhangyun{at}sdu.edu.cn , and Ying H. Shen, hyshen{at}bcm.edu . X.-N.L. and J.S. contributed equally to this study. Abstract 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. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received October 31, 2008. Accepted June 28, 2009. © 2009 by the American Diabetes Association.
Sprache
Englisch
Identifikatoren
ISSN: 0012-1797
eISSN: 1939-327X
DOI: 10.2337/db08-1512
Titel-ID: cdi_gale_incontextcollege_GICCO_A209234965
Format
–
Schlagworte
Aminoimidazole Carboxamide - analogs & derivatives
,
Aminoimidazole Carboxamide - pharmacology
,
AMP-Activated Protein Kinases - metabolism
,
Animals
,
Antioxidants
,
Aorta
,
Apolipoproteins E - deficiency
,
Apolipoproteins E - genetics
,
Cardiovascular diseases
,
Cardiovascular system
,
Care and treatment
,
Causes of
,
DNA Primers
,
Endothelium, Vascular - drug effects
,
Endothelium, Vascular - metabolism
,
Fatty acids
,
Fatty Acids - pharmacology
,
Forkhead Box Protein O3
,
Forkhead Transcription Factors - metabolism
,
Genetic aspects
,
Growth factors
,
Humans
,
Kinases
,
Male
,
Metabolic syndrome
,
Mice
,
Mice, Knockout
,
Original
,
Oxidative stress
,
Palmitic Acid - pharmacology
,
Physiological aspects
,
Plasmids - drug effects
,
Quantitative analysis
,
Reactive Oxygen Species - metabolism
,
Research design
,
Reverse Transcriptase Polymerase Chain Reaction
,
Ribonucleotides - pharmacology
,
Risk factors
,
RNA, Messenger - genetics
,
RNA, Small Interfering - genetics
,
Thioredoxin
,
Thioredoxins
,
Thioredoxins - genetics
,
Transcription factors
,
Up-Regulation
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