Angiotensin II inhibits insulin-stimulated GLUT4 translocation and Akt activation through tyrosine nitration-dependent mechanisms.
Angiotensin II inhibits insulin-stimulated GLUT4 translocation and Akt activation through tyrosine nitration-dependent mechanisms.
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DOI：
10.1371/journal.pone.0010070
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发表时间：
2010-04-07
期刊：
影响因子：
3.7
通讯作者：
Bottari SP
中科院分区：
文献类型：
--
作者：
Csibi A;Communi D;Müller N;Bottari SP
血管紧张素II(Ang II)通过抑制胰岛素代谢，增强其营养作用，在胰岛素抵抗和糖尿病的发病机制中发挥重要作用。虽然涉及的确切机制仍不清楚，但它们似乎与氧化应激增加有关，并依赖于氧化应激增加。我们发现Ang II以NO和O2.−依赖的方式阻断L6肌管中胰岛素依赖的Glut4易位，提示过氧亚硝酸盐参与其中。Ang II诱导MAP激酶ERK1/2和蛋白激酶B/Akt(Akt)酪氨酸硝化的能力证实了这一假说。ERK1/2在Thr和Tyr上的磷酸化和随后的激活需要ERK1/2的酪氨酸硝化，而它完全抑制Ser473和Thr308上的Akt磷酸化及其活性。SIN-1在体外完全阻断GSK3α磷酸化的能力证实了硝化对Akt活性的抑制作用。抑制一氧化氮合酶和NAD(P)过氧化氢酶，以及杨梅素清除自由基，可以恢复Ang II诱导的胰岛素刺激的Akt磷酸化和GLUT4转位。抑制ERK激活的激酶MEK也能恢复胰岛素刺激的Akt磷酸化和GLUT4转位，表明这些激酶调节Akt的激活。我们发现ERK1/2的保守硝化位点位于它们在Tyr156/139上的激活区，靠近它们的活性部位Asp166/149，这与它们被硝化激活的许可功能是一致的。综上所述，我们的数据表明，Ang II至少通过两条途径抑制胰岛素介导的GLUT4在骨骼肌模型中的转位：第一，通过瞬时激活ERK1/2，抑制IRS-1/2；第二，通过直接抑制Akt的硝化。这些观察表明，不仅氧化应激，而且硝化应激在胰岛素抵抗的发病机制中起着关键作用。它们强调了蛋白质硝化作为调节Ang II和胰岛素信号通路的主要机制的作用，尤其是作为蛋白激酶活性的关键调节因子。
Angiotensin II (Ang II) plays a major role in the pathogenesis of insulin resistance and diabetes by inhibiting insulin's metabolic and potentiating its trophic effects. Whereas the precise mechanisms involved remain ill-defined, they appear to be associated with and dependent upon increased oxidative stress. We found Ang II to block insulin-dependent GLUT4 translocation in L6 myotubes in an NO- and O2 .−-dependent fashion suggesting the involvement of peroxynitrite. This hypothesis was confirmed by the ability of Ang II to induce tyrosine nitration of the MAP kinases ERK1/2 and of protein kinase B/Akt (Akt). Tyrosine nitration of ERK1/2 was required for their phosphorylation on Thr and Tyr and their subsequent activation, whereas it completely inhibited Akt phosphorylation on Ser473 and Thr308 as well as its activity. The inhibitory effect of nitration on Akt activity was confirmed by the ability of SIN-1 to completely block GSK3α phosphorylation in vitro. Inhibition of nitric oxide synthase and NAD(P)Hoxidase and scavenging of free radicals with myricetin restored insulin-stimulated Akt phosphorylation and GLUT4 translocation in the presence of Ang II. Similar restoration was obtained by inhibiting the ERK activating kinase MEK, indicating that these kinases regulate Akt activation. We found a conserved nitration site of ERK1/2 to be located in their kinase domain on Tyr156/139, close to their active site Asp166/149, in agreement with a permissive function of nitration for their activation. Taken together, our data show that Ang II inhibits insulin-mediated GLUT4 translocation in this skeletal muscle model through at least two pathways: first through the transient activation of ERK1/2 which inhibit IRS-1/2 and second through a direct inhibitory nitration of Akt. These observations indicate that not only oxidative but also nitrative stress play a key role in the pathogenesis of insulin resistance. They underline the role of protein nitration as a major mechanism in the regulation of Ang II and insulin signaling pathways and more particularly as a key regulator of protein kinase activity.
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