Reactive nitrogen species is required for the activation of the AMP-activated protein kinase by statin in vivo (Retracted article. See vol. 294, pg. 10742, 2019)
Reactive nitrogen species is required for the activation of the AMP-activated protein kinase by statin in vivo (Retracted article. See vol. 294, pg. 10742, 2019)
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DOI：
10.1074/jbc.m803020200
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发表时间：
2008-07-18
影响因子：
4.8
通讯作者：
Zou, Ming-Hui
中科院分区：
文献类型：
--
作者：
Choi, Hyoung Chul;Song, Ping;Zou, Ming-Hui
腺苷酸活化蛋白激酶（AMPK）介导了他汀类药物对血管功能的有益作用，但其生化机制尚不完全清楚。这项研究的目的是确定他汀类药物如何激活AMPK。将融合的牛主动脉内皮细胞暴露于辛伐他汀（他汀类药物）剂量依赖性地增加AMPK在Thr（172）的磷酸化和AMPK的活性，这与LKB 1在Ser（428）磷酸化和LKB 1核输出的检测增加平行。此外，他汀类药物治疗显示增加蛋白激酶C（PKC）-zeta活性和Thr（410）/Thr（403）处的PKC-zeta磷酸化。一致地，通过药理学或遗传操作抑制PKC-zeta废除了他汀类药物增强的LKB 1丝氨酸428磷酸化，阻断了LKB 1核输出，并阻止了随后的AMPK激活。同样，在C57 BL/6 J小鼠体内转染PKC-zeta特异性小干扰RNA显著减弱了他汀类药物增强的AMPK-Thr（172）、乙酰辅酶A羧化酶（ACC）-Ser（79）和LKB 1-Ser（428）磷酸化。此外，他汀类药物显著增加了活性氧，而mito-TEMPOL（一种超氧化物歧化酶模拟物）的预孵育消除了他汀类药物增强的AMPK-Thr（172）和ACC-Ser（79）磷酸化。最后，在C57 BL/6 J小鼠体内给予他汀类药物增加了3-硝基酪氨酸和AMPK和ACC的磷酸化，但在内皮型一氧化氮合酶缺乏的小鼠中没有。总之，我们的数据表明他汀类药物激活AMPK是过氧亚硝基介导的，但依赖于PKC-zeta。
The AMP-activated protein kinase (AMPK) is reported to mediate the beneficial effects of statin on the vascular functions, but the biochemical mechanisms are incompletely understood. The aim of the study was to determine how statin activates AMPK. Exposure of confluent bovine aortic endothelial cells to simvastatin (statin) dose-dependently increased phosphorylation of AMPK at Thr(172) and activities of AMPK, which was in parallel with increased detection of both LKB1 phosphorylation at Ser(428) and LKB1 nuclear export. Furthermore, statin treatment was shown to increase protein kinase C (PKC)-zeta activity and PKC-zeta phosphorylation at Thr(410)/Thr(403). Consistently, inhibition of PKC-zeta either by pharmacological or genetic manipulations abolished statin-enhanced LKB1 phosphorylation at Ser428, blocked LKB1 nucleus export, and prevented the subsequent activation of AMPK. Similarly, in vivo transfection of PKC-zeta-specific small interfering RNA in C57BL/6J mice significantly attenuated statin-enhanced phosphorylation of AMPK-Thr(172), acetyl-CoA carboxylase (ACC)-Ser(79), and LKB1-Ser(428). In addition, statin significantly increased reactive oxygen species, whereas preincubation of mito-TEMPOL, a superoxide dismutase mimetic, abolished statin-enhanced phosphorylation of both AMPK-Thr(172) and ACC-Ser(79). Finally, in vivo administration of statin increased 3-nitrotyrosine and the phosphorylation of AMPK and ACC in C57BL/6J mice but not in mice deficient in endothelial nitric-oxide synthase. Taken together, our data suggest thatAMPKactivation by statin is peroxynitrite-mediated but PKC-zeta-dependent.