Activation of AMP-activated Protein Kinase α1 Alleviates Endothelial Cell Apoptosis by Increasing the Expression of Anti-apoptotic Proteins Bcl-2 and Survivin (Publication with Expression of Concern. See vol. 294, pg. 10021, 2019) (Withdrawn Publication. See vol. 295, pg. 671, 2020)
Activation of AMP-activated Protein Kinase α1 Alleviates Endothelial Cell Apoptosis by Increasing the Expression of Anti-apoptotic Proteins Bcl-2 and Survivin (Publication with Expression of Concern. See vol. 294, pg. 10021, 2019) (Withdrawn Publication. See vol. 295, pg. 671, 2020)
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DOI：
10.1074/jbc.m110.102491
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发表时间：
2010-05-14
影响因子：
4.8
通讯作者：
Zou, Ming-Hui
中科院分区：
文献类型：
--
作者：
Liu, Chao;Liang, Bin;Zou, Ming-Hui
越来越多的证据表明，AMP 激活蛋白激酶 (AMPK) 的激活可在多种类型的细胞中发挥抗凋亡作用。然而，潜在的机制仍然不明确。本研究的目的是确定 AMPK 如何抑制暴露于缺氧和葡萄糖剥夺 (OGD) 的内皮细胞的凋亡。在经过或不经过 OGD 处理的培养内皮细胞和小鼠颈总动脉中检测 AMPK 活性、NF-κ B 激活和内皮细胞凋亡。 OGD早在30分钟就显着激活了AMPK，并且AMPK活性在OGD 2小时时达到最大。直到 OGD 2 小时才检测到内皮细胞凋亡，但在 OGD 治疗 6 小时时内皮细胞凋亡显着升高。此外，化合物C对AMPK的抑制或显性失活AMPK（AMPK-DN）的过度表达加剧，而药物（氨基咪唑甲酰胺核糖核苷酸（AICAR））或遗传手段（组成型活性AMPK的过度表达）激活AMPK抑制了OGD引起的内皮细胞凋亡。与此同时，AMPK 激活增加了 Bcl-2 和 Survivin（两种有效的抗凋亡蛋白）的表达。此外，AMPK 激活显着增强 I kappa B α 激酶激活、NF-kappa B 核易位和 NF-kappa B 的 DNA 结合活性。同样，选择性抑制 NF-kappa B 可消除 OGD 增强的 Bcl-2 和 Survivin 表达，从而加剧 OGD 引起的内皮细胞凋亡。最后，我们发现 AMPK α 1 的基因缺失（而非 AMPK α 2）抑制了 OGD 增强的 NF-κ B 激活、Bcl-2 和 Survivin 的表达以及内皮细胞凋亡。总体而言，我们的结果表明，AMPK α 1（而非 AMPK α 2）激活通过增加 NF-κ B 介导的抗凋亡蛋白（Bcl-2 和 Survivin）表达和细胞内 ATP 含量来促进细胞存活。
Accumulating evidence suggests that AMP-activated protein kinase (AMPK) activation exerts anti-apoptotic effects in multiple types of cells. However, the underlying mechanisms remain poorly defined. The aim of the present study was to determine how AMPK suppresses apoptosis in endothelial cells exposed to hypoxia and glucose deprivation (OGD). AMPK activity, NF-kappa B activation, and endothelial cell apoptosis were assayed in cultured endothelial cells and mouse common carotid artery with or without OGD treatment. OGD markedly activated AMPK as early as 30 min, and AMPK activity reached maximal at 2 h of OGD. Endothelial apoptosis was not detected until 2 h of OGD but became markedly elevated at 6 h of OGD treatment. Furthermore, AMPK inhibition by Compound C or overexpression of dominant negative AMPK(AMPK-DN) exacerbated, whereas AMPK activation by pharmacologic (aminoimidazole carboxamide ribonucleotide (AICAR)) or genetic means (overexpression of constitutively active AMPK) suppressed endothelial cell apoptosis caused by OGD. Concomitantly, AMPK activation increased the expression of both Bcl-2 and Survivin, two potent anti-apoptotic proteins. Furthermore, AMPK activation significantly enhanced I kappa B alpha kinase activation, NF-kappa B nuclear translocation, and DNA binding activity of NF-kappa B. Consistently, selective inhibition of NF-kappa B, which abolished OGD-enhanced expression of Bcl-2 and Survivin, accentuated endothelial apoptosis caused by OGD. Finally, we found that genetic deletion of the AMPK alpha 1, but not AMPK alpha 2, suppressed OGD-enhanced NF-kappa B activation, the expression of Bcl-2 and Survivin, and endothelial apoptosis. Overall, our results suggest that AMPK alpha 1, but not AMPK alpha 2 activation, promotes cell survival by increasing NF-kappa B-mediated expression of anti-apoptotic proteins (Bcl-2 and Survivin) and intracellular ATP contents.