Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo.
Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo.
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作者：
Tan Y;Ichikawa T;Li J;Si Q;Yang H;Chen X;Goldblatt CS;Meyer CJ;Li X;Cai L;Cui T
氧化应激与心脏胰岛素抵抗有关，这是心力衰竭的一个关键危险因素，但直接证据仍然缺失。本研究探讨了氧化应激与胰岛素抵抗之间的因果关系，重点是氧化还原敏感转录因子NF-E2相关因子2（Nrf 2）在体外和体内心肌细胞中的调节作用。慢性处理HL-1成人心肌细胞与过氧化氢导致胰岛素抵抗，反映了一个显着抑制胰岛素诱导的葡萄糖摄取。这与细胞外信号相关激酶（ERK）的过度磷酸化有关。ERK抑制剂U 0126可增强胰岛素敏感性，减轻氧化应激诱导的胰岛素抵抗，而PI 3 K抑制剂LY 294002则可加重胰岛素抵抗。此外，胰岛素增加Nrf 2的转录活性，这是由LY 294002阻断，但由U 0126增强。Nrf 2的腺病毒过表达的Nrf 2的强制激活抑制ERK活性的增加，并恢复钝化的胰岛素敏感性对葡萄糖摄取的心肌细胞中，慢性处理过氧化氢。在链脲佐菌素诱导的糖尿病小鼠和糖尿病患者的心脏中，Nrf 2表达显著降低沿着3-硝基酪氨酸积累和ERK磷酸化的显著增加，而在心脏特异性过表达强效抗氧化剂金属硫蛋白的糖尿病小鼠的心脏中未观察到这些致病性变化。在体外和体内心肌细胞中，Nrf 2通过其激活剂Dh 404上调可防止过氧化氢和糖尿病诱导的ERK激活和胰岛素信号转导下调。ERK介导的Nrf 2活性抑制导致成年心肌细胞氧化应激诱导的胰岛素抵抗和糖尿病心脏葡萄糖利用下调。
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. 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 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. 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.