Diabetic Downregulation of Nrf2 Activity via ERK Contributes to Oxidative Stress-Induced Insulin Resistance in Cardiac Cells In Vitro and In Vivo

doi:10.2337/db10-1164

科研成果详情

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	Tan, Yi1,2; Ichikawa, Tomonaga 3; Li, Jinqing 3; Si, Qiusheng 4; Yang, Huaitao 4; Chen, Xiangbai 4; Goldblatt, Curtis S.4; Meyer, Colin J.5; Li, Xiaokun1; Cai, Lu1,2; Cui, Taixing 1,3
发表日期	2011-02
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
页数	9
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
URL	查看原文
PubMed ID	21270272
PMC记录号	PMC3028364
SCOPUSEID	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
通讯作者地址	[Cai, Lu]Chinese-American Research Institute for Diabetic Complications,Wenzhou Medical College,China
Scopus学科分类	Internal Medicine;Endocrinology, Diabetes and Metabolism
TOP期刊	TOP期刊
引用统计	被引频次：285[WOS] [WOS记录] [WOS相关记录]
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	Cai, Lu
作者单位	1.Chinese-American Research Institute for Diabetic Complications,Wenzhou Medical College,China; 2.Department of Pediatrics,University of Louisville,United States; 3.Department of Cell Biology and Anatomy,University of South Carolina School of Medicine,United States; 4.Department of Pathology,Memorial Medical Center,United States; 5.Reata Pharmaceuticals,United States
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
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.