题名 | Diabetic Downregulation of Nrf2 Activity via ERK Contributes to Oxidative Stress-Induced Insulin Resistance in Cardiac Cells In Vitro and In Vivo |
作者 | |
发表期刊 | DIABETES 影响因子和分区 |
语种 | 英语 |
原始文献类型 | Article |
其他关键词 | CONTRACTILE DYSFUNCTION ; NITROSATIVE DAMAGE ; HEART-FAILURE ; HL-1 CELLS ; METALLOTHIONEIN ; PATHWAY ; CARDIOMYOPATHY ; MUSCLE ; MICE ; OVEREXPRESSION |
摘要 | OBJECTIVE-Oxidative stress is implicated in cardiac insulin resistance, a critical risk factor for cardiac failure, but the direct evidence remains missing. This study explored a causal link between oxidative stress and insulin resistance with a focus on a regulatory role of redox sensitive transcription factor NF-E2-related factor 2 (Nrf2) in the cardiac cells in vitro and in vivo. RESEARCH DESIGN AND METHODS-Chronic treatment of HL-1 adult cardiomyocyte with hydrogen peroxide led to insulin resistance, reflected by a significant suppression of the insulin-induced glucose uptake. This was associated with an exaggerated phosphorylation of extracellular signal-related kinase (ERK). Although U0126, an ERK inhibitor, enhanced insulin sensitivity and attenuated oxidative stress-induced insulin resistance, LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), worsened the insulin resistance. Moreover, insulin increased Nrf2 transcriptional activity, which was blocked by LY294002 but enhanced by U0126. Forced activation of Nrf2 by adenoviral overexpression of Nrf2 inhibited the increased ERK activity and recovered the blunted insulin sensitivity on glucose uptake in cardiomyocytes that were chronically treated with H2O2. In the hearts of streptozotocin-induced diabetic mice and diabetic patients Nrf2 expression significantly decreased along with significant increases in 3-nitrotyrosine accumulation and ERK phosphorylation, whereas these pathogenic changes were not observed in the heart of diabetic mice with cardiac-specific overexpression of a potent antioxidant metallothionein. Upregulation of Nrf2 by its activator, Dh404, in cardiomyocytes in vitro and in vivo prevented hydrogen peroxide- and diabetes-induced ERK activation and insulin-signaling downregulation. CONCLUSIONS-ERK-mediated suppression of Nrf2 activity leads to the oxidative stress-induced insulin resistance in adult cardiomyocytes and downregulated glucose utilization in the diabetic heart. Diabetes 60:625-633, 2011 |
资助项目 | American Heart AssociationAmerican Heart Association [0865101E]; American Diabetes AssociationAmerican Diabetes Association [05-07-CD-02]; Wenzhou Medical College; Zhejiang Provincial Extremely Key Subject Building Project Pharmacology and Biochemical Pharmaceutics 2009 |
出版者 | AMER DIABETES ASSOC |
出版地 | ALEXANDRIA |
ISSN | 0012-1797 |
EISSN | 1939-327X |
卷号 | 60期号:2页码:625-633 |
DOI | 10.2337/db10-1164 |
WOS类目 | Endocrinology & Metabolism |
WOS研究方向 | Endocrinology & Metabolism |
WOS记录号 | WOS:000287172100033 |
收录类别 | SCIE ; PUBMED ; SCOPUS |
发表日期 | 2011-02 |
URL | 查看原文 |
Pubmed记录号 | 21270272 |
PMC记录号 | PMC3028364 |
Scopus记录号 | 2-s2.0-79551575483 |
ESI高被引论文 | 2020-01 ; 2020-03 ; 2020-05 ; 2020-09 ; 2020-11 ; 2021-01 ; 2021-03 ; 2021-05 ; 2021-07 ; 2021-09 ; 2021-11 ; 2022-01 |
自科自定义期刊分类 | T3(B)类 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | https://kms.wmu.edu.cn/handle/3ETUA0LF/11391 |
专题 | 温州医科大学 |
通讯作者 | Cui, Taixing |
作者单位 | 1.Wenzhou Med Coll, Chinese Amer Res Inst Diabet Complicat, Wenzhou, Zhejiang, Peoples R China; 2.Univ Louisville, Dept Pediat, Louisville, KY 40292 USA; 3.Univ S Carolina, Sch Med, Dept Cell Biol & Anat, Columbia, SC USA; 4.Mem Med Ctr, Dept Pathol, Johnstown, PA USA; 5.Reata Pharmaceut, Irving, TX USA |
第一作者单位 | 温州医科大学 |
通讯作者单位 | 温州医科大学 |
第一作者的第一单位 | 温州医科大学; 温州医科大学 |
推荐引用方式 GB/T 7714 | Tan, Yi,Ichikawa, Tomonaga,Li, Jinqing,et al. Diabetic Downregulation of Nrf2 Activity via ERK Contributes to Oxidative Stress-Induced Insulin Resistance in Cardiac Cells In Vitro and In Vivo[J]. DIABETES,2011,60(2):625-633. |
APA | Tan, Yi., Ichikawa, Tomonaga., Li, Jinqing., Si, Qiusheng., Yang, Huaitao., ... & Cui, Taixing. (2011). Diabetic Downregulation of Nrf2 Activity via ERK Contributes to Oxidative Stress-Induced Insulin Resistance in Cardiac Cells In Vitro and In Vivo. DIABETES, 60(2), 625-633. |
MLA | Tan, Yi,et al."Diabetic Downregulation of Nrf2 Activity via ERK Contributes to Oxidative Stress-Induced Insulin Resistance in Cardiac Cells In Vitro and In Vivo".DIABETES 60.2(2011):625-633. |
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