title: Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo.
abstract: 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.
  
  
  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 over-expression of Nrf2 inhibited the increased ERK activity and recovered the blunted insulin sensitivity on glucose uptake in cardiomyocytes that were chronically treated with H(2)O(2). 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.
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical College, Wenzhou, Zhejiang, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.forename: Tomonaga
authors.initials: T
authors.lastname: Ichikawa
authors.forename: Jinqing
authors.initials: J
authors.lastname: Li
authors.forename: Qiusheng
authors.initials: Q
authors.lastname: Si
authors.forename: Huaitao
authors.initials: H
authors.lastname: Yang
authors.forename: Xiangbai
authors.initials: X
authors.lastname: Chen
authors.forename: Curtis S
authors.initials: CS
authors.lastname: Goldblatt
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Meyer
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
authors.forename: Taixing
authors.initials: T
authors.lastname: Cui
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D007328:Insulin; D051267:NF-E2-Related Factor 2; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose