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

作者：Yi Tan, Tomonaga Ichikawa, Jinqing Li, Qiusheng Si, Huaitao Yang, Xiangbai Chen, Curtis S. Goldblatt, Colin J. Meyer, Xiaokun Li, Lu Cai, Taixing Cui · 发表于：Diabetes · 年份：2011 · DOI：10.2337/db10-1164 · 被引用次数：401 · 研究领域：Genomics, phytochemicals, and oxidative stress、Cardiovascular Function and Risk Factors、Cardiac Fibrosis and Remodeling

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 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 obse...