Endothelial AMPK activation induces mitochondrial biogenesis and stress adaptation via eNOS-dependent mTORC1 signaling.
Endothelial AMPK activation induces mitochondrial biogenesis and stress adaptation via eNOS-dependent mTORC1 signaling.
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DOI：
10.1016/j.niox.2016.03.003
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发表时间：
2016-05-01
期刊：
影响因子：
--
通讯作者：
Keaney JF Jr
中科院分区：
文献类型：
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作者：
Li C;Reif MM;Craige SM;Kant S;Keaney JF Jr
代谢应激感受器，如AMP激活的蛋白激酶(AMPK)，已知在低等生物中具有压力适应和延长寿命的作用。这项研究表明，激活内皮细胞中的代谢应激感受器AMP激活的蛋白激酶(AMPK)，通过促进线粒体的生物生成和压力适应，有助于维持正常的细胞功能。为了更好地确定AMPK促进内皮细胞抗应激的机制，我们使用5-氨基咪唑-4-甲酰胺核苷(AICAR)慢性激活AMPK，并观察了对野生型小鼠内皮细胞线粒体生物发生的刺激，但对内皮型一氧化氮合酶基因敲除(eNOS-Null)小鼠的内皮没有刺激作用。有趣的是，AICAR增强的线粒体生物发生被哺乳动物靶标雷帕霉素复合体1(MTORC1)抑制剂雷帕霉素阻断。此外，AICAR通过野生型而不是eNOS缺失的内皮细胞中已知的下游效应器的磷酸化来刺激mTORC1。综上所述，这些数据表明eNOS需要将AMPK激活与mTORC1偶联，从而促进内皮细胞中线粒体的生物发生和应激适应。这些数据提示了一种新的mTORC1激活机制，这对血管功能障碍的研究具有重要意义。
Metabolic stress sensors like AMP-activated protein kinase (AMPK) are known to confer stress adaptation and promote longevity in lower organisms. This study demonstrates that activating the metabolic stress sensor AMP-activated protein kinase (AMPK) in endothelial cells helps maintain normal cellular function by promoting mitochondrial biogenesis and stress adaptation. To better define the mechanisms whereby AMPK promotes endothelial stress resistance, we used 5-aminoimidazole-4-carboxamide riboside (AICAR) to chronically activate AMPK and observed stimulation of mitochondrial biogenesis in wild type mouse endothelium, but not in endothelium from endothelial nitric oxide synthase knockout (eNOS-null) mice. Interestingly, AICAR-enhanced mitochondrial biogenesis was blocked by pretreatment with the mammalian target of rapamycin complex 1 (mTORC1) inhibitor, rapamycin. Further, AICAR stimulated mTORC1 as determined by phosphorylation of its known downstream effectors in wild type, but not eNOS-null, endothelial cells. Together these data indicate that eNOS is needed to couple AMPK activation to mTORC1 and thus promote mitochondrial biogenesis and stress adaptation in the endothelium. These data suggest a novel mechanism for mTORC1 activation that is significant for investigations in vascular dysfunction.