Ameliorative effects of indomethacin at different concentrations on endothelial insulin resistance through two distinct pathways.
Ameliorative effects of indomethacin at different concentrations on endothelial insulin resistance through two distinct pathways.
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不同浓度的吲哚美辛通过两种不同的途径对内皮胰岛素抵抗产生改善作用。
DOI：
10.1016/j.biopha.2018.07.069
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发表时间：
2018-10
影响因子：
7.5
通讯作者：
Huang Qiren
中科院分区：
文献类型：
--
作者：
Xian Tao;Gan Yuyang;Lu Yi;Wang Mengxi;Yuan Wanwan;Zhou Yumeng;Chen Junye;Wang Kun;Xiong Shaofeng;Huang Qiren
吲哚美辛(IDMT)是一种环氧合酶-2(COX-2)的非选择性抑制剂，具有重要的抗炎和镇痛作用，常用于治疗风湿性和类风湿性关节炎。此外，各种文献报道，IDMT是过氧化物酶体增殖物激活受体γ(PPARγ)的合成配体。罗格列酮(RSG)是一种胰岛素增敏剂，也是一种合成配体，临床上用于治疗2型糖尿病。然而，到目前为止，关于IDMT是否改善血管内皮细胞胰岛素抵抗(IR)知之甚少。因此，本研究旨在探讨IDMT对内皮细胞IR的影响及其机制。我们目前的结果表明，IDMT以浓度和时间依赖的方式改善高糖和高脂浓度(HG/HF)诱导的内皮细胞IR。有趣的是，我们进一步发现0.25 mM的iDMT可显著诱导PPARγ、AKT和内皮型一氧化氮合酶(ENOS)的表达，但不能显著逆转HG/HF诱导的COX-2、抑制性κB激酶(IKK)和肿瘤坏死因子α(TNα)的表达水平；而1.0 mM的iDMT与0.25 mM的iDMT的作用相反。因此，我们认为IDMT通过两条不同的途径改善HG/HF诱导的内皮细胞IR，即低浓度的IDMT通过PPARγ-AKT-eNOS途径和高浓度的主要通过IKK-COX-2/肿瘤坏死因子α途径。这一发现可能为IDMT治疗IR相关疾病提供了一种新的临床用途。
Indomethacin (IDMT), a non-selective inhibitor of cycloxygenase-2 (COX-2), plays important roles in anti-inflammation and analgesia and it is commonly used to treat the patients with rheumatic and rheumatoid arthritis. Besides, various literatures reported that IDMT is a synthetic ligand of peroxisome proliferator activated receptor gamma (PPARγ). Rosiglitazone (RSG), an insulin-sensitizer, is also a synthetic ligand and applied clinically to cure the patients with type 2 diabetes mellitus. However, up to date little is known about whether IDMT ameliorates endothelial insulin resistance (IR). Accordingly, the purpose of this study is to investigate the effects of IDMT on endothelial IR and its underlying mechanism. Our present results showed that IDMT improved the endothelial IR induced by high glucose and fat concentration (HG/HF) in a concentration and time-dependent manner. Intriguingly, we further identified that 0.25 mM of IDMT noticeably induced the expression levels of PPARγ, AKT and endothelial nitric oxide synthase (eNOS) but failed to notably reverse the increases in expression levels of COX-2, inhibitory κB kinase (IKK) and tumor necrosis factor alpha (TNFα) induced by HG/HF; whereas 1.0 mM of IDMT exerted opposite effects compared with 0.25 mM of IDMT. Therefore, we conclude that IDMT ameliorates the endothelial IR induced by HG/HF through two distinct pathways, i.e., a lower concentration of IDMT through a PPARγ-AKT-eNOS pathway while a higher concentration mainly via an IKK-COX-2/TNFα pathway. The findings might provide a novel clinical use for IDMT to cure IR-related disorders.
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影响因子：
2.9
作者：
Alemán-González-Duhart D;Tamay-Cach F;Álvarez-Almazán S;Mendieta-Wejebe JE
通讯作者：
Mendieta-Wejebe JE
影响因子：
16.2
作者：
Ford, ES
通讯作者：
Ford, ES
影响因子：
5
作者：
Lucas, Sylvia
通讯作者：
Lucas, Sylvia
影响因子：
4.8
作者：
Jiang, Youde;Thakran, Shalini;Steinle, Jena J.
通讯作者：
Steinle, Jena J.
影响因子：
4.4
作者：
Badeau, Robert M.;Honka, Miikka-Juhani;Nuutila, Pirjo
通讯作者：
Nuutila, Pirjo