Involvement of increased endogenous asymmetric dimethylarginine in the hepatic endoplasmic reticulum stress of type 2 diabetic rats.
Involvement of increased endogenous asymmetric dimethylarginine in the hepatic endoplasmic reticulum stress of type 2 diabetic rats.
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内源性不对称二甲基精氨酸增加对 2 型糖尿病大鼠肝内质网应激的影响。
DOI：
10.1371/journal.pone.0097125
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Xiong Y
中科院分区：
文献类型：
--
作者：
Leng YP;Qiu N;Fang WJ;Zhang M;He ZM;Xiong Y
越来越多的证据表明，内质网 (ER) 应激会导致胰岛素抵抗，而胰岛素抵抗在 2 型糖尿病 (T2DM) 的发展中发挥着重要作用。内源性一氧化氮合酶 (NOS) 抑制剂、不对称二甲基精氨酸 (ADMA) 的积累与胰岛素抵抗、T2DM 和糖尿病心血管并发症有关，但其机制尚未阐明。本研究旨在确定内源性ADMA升高是否与2型糖尿病大鼠肝脏ER应激有关，验证其因果关系，并阐明ADMA诱导大鼠肝细胞ER应激的潜在机制。测量免疫球蛋白结合蛋白 (Bip) 转录、真核起始因子 2α 激酶 (eIF2α) 磷酸化、X box 结合蛋白 1 (XBP-1) mRNA 剪接和 C/EBP 同源蛋白 (CHOP) 表达以反映 ER 应激。检测ADMA和亚硝酸盐/硝酸盐的含量以及NOS和二甲基精氨酸二甲氨基水解酶(DDAH)的活性或表达，以显示DDAH/ADMA/NOS/NO途径的变化。通过分析脂质过氧化产物丙二醛含量和抗氧化酶超氧化物歧化酶活性来评价氧化应激。 2 型糖尿病大鼠的肝脏中引发了 ER 应激，表现为 Bip 转录、eIF2α 磷酸化、XBP-1 剪接和 CHOP 表达的增加，所有这些都与肝脏中血清 ADMA 的升高、NO 生成、NOS 和 DDAH 活性的抑制同时发生。肝细胞暴露于 ADMA 或过氧化氢也会诱发 ER 应激，这与 NO 产生的抑制和氧化应激的增加有关。用抗氧化剂吡咯烷二硫代氨基甲酸酯处理肝细胞不仅减少了 ADMA 诱导的氧化应激和 NO 产生的抑制，而且还减少了 ADMA 触发的 ER 应激。这些结果表明，内源性 ADMA 增加会导致 2 型糖尿病大鼠的肝脏 ER 应激，并且 ADMA 诱导 ER 应激的机制可能与通过 NOS 解偶联产生的氧化应激有关。
Increasing evidence suggested that endoplasmic reticulum (ER) stress contributes to insulin resistance, which plays an important role in the development of type 2 diabetes mellitus (T2DM). Accumulation of endogenous nitric oxide synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), is associated with insulin resistance, T2DM, and diabetic cardiovascular complications, although the mechanisms have not been elucidated. This study was to determine whether elevated endogenous ADMA is involved in hepatic ER stress of type 2 diabetic rats, verify their causal relationship, and elucidate the potential mechanism underlying ADMA induced ER stress in rat hepatocytes. Immunoglobulin binding protein (Bip) transcription, eukaryotic initiation factor 2α kinase (eIF2α) phosphorylation, X box-binding protein-1 (XBP-1) mRNA splicing and C/EBP homologues protein (CHOP) expression were measured to reflect ER stress. Contents of ADMA and nitrite/nitrate as well as activities or expression of NOS and dimethylarginine dimethylaminohydrolase (DDAH) were detected to show the changes in DDAH/ADMA/NOS/NO pathway. The lipid peroxidation product malondialdehyde content and antioxidant enzyme superoxide dismutase activity were analyzed to evaluate oxidative stress. ER stress was provoked in the liver of type 2 diabetic rats, as expressed by increases of Bip transcription, eIF2α phosphorylation, XBP-1 splicing and CHOP expression, all of which were in parallel with the elevation of serum ADMA, suppression of NO generation, NOS and DDAH activities in the liver. Exposure of hepatocytes to ADMA or hydrogen peroxide also induced ER stress, which was associated with the inhibition of NO production and increase of oxidative stress. Treatment of hepatocytes with antioxidant pyrrolidine dithiocarbamate not only decreased ADMA-induced oxidative stress and inhibition of NO production but also reduced ADMA-triggered ER stress. These results indicate that increased endogenous ADMA contributes to hepatic ER stress in type 2 diabetic rats, and the mechanism underlying ADMA-induced ER stress may relate to oxidative stress via NOS uncoupling.
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影响因子：
11.4
作者：
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通讯作者：
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