Activation of the AMP-activated protein kinase (AMPK) by nitrated lipids in endothelial cells.
Activation of the AMP-activated protein kinase (AMPK) by nitrated lipids in endothelial cells.
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DOI：
10.1371/journal.pone.0031056
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zou MH
中科院分区：
文献类型：
--
作者：
Wu Y;Dong Y;Song P;Zou MH
AMP活化蛋白激酶（AMPK）是内皮细胞代谢和功能稳态的重要调节因子。在这里，我们研究了硝酸油酸（OA-NO2）对AMPK的调节，并研究了其对内皮功能的影响。用OA-NO2处理牛主动脉内皮细胞（BAECs）可诱导AMPK-Thr 172磷酸化和AMPK活性显著增加，以及血红素加氧酶（HO）-1和缺氧诱导因子（HIF）-1α表达上调。HO-1或HIF-1α的药理学抑制或基因消融可消除OA-NO2诱导的AMPK磷酸化。OA-NO2诱导细胞外信号调节激酶（ERK）1/2磷酸化的显著增加，其被HO-1抑制剂锌次卟啉IX 2，4-二乙二醇（ZnBG）废除。用UO 126或PD 98059抑制ERK 1/2可减少但不能消除OA-NO2诱导的HIF-1α上调，表明OA-NO2/HO-1诱导的HIF-1α诱导部分依赖于ERK 1/2活性。此外，OA-NO2增加内皮细胞内Ca 2+，这种作用被HIF-1α抑制剂YC-1和HIF-1α siRNA抑制。这些结果暗示HIF-1α参与了该过程。使用Ca 2 +/钙调蛋白依赖性蛋白激酶激酶（CaMKK）抑制剂STO-609、选择性CaMKII抑制剂KN-93和亚型特异性siRNA的实验表明，OA-NO2诱导的AMPK磷酸化依赖于CaMKKβ。总之，这些结果表明，OA-NO2通过HO-1依赖性机制激活内皮细胞中的AMPK，该机制增加HIF-1α蛋白表达和Ca 2 +/CaMKKβ激活。
The AMP-activated protein kinase (AMPK) is an important regulator of endothelial metabolic and functional homeostasis. Here, we examined the regulation of AMPK by nitrated oleic acid (OA-NO2) and investigated the implications in endothelial function. Treatment of bovine aortic endothelial cells (BAECs) with OA-NO2 induced a significant increase in both AMPK-Thr172 phosphorylation and AMPK activity as well as upregulation of heme oxygenase (HO)-1 and hypoxia-inducible factor (HIF)-1α. Pharmacologic inhibition or genetic ablation of HO-1 or HIF-1α abolished OA-NO2-induced AMPK phosphorylation. OA-NO2 induced a dramatic increase in extracellular signal-regulated kinase (ERK)1/2 phosphorylation that was abrogated by the HO-1 inhibitor, zinc deuteroporphyrin IX 2,4-bis-ethylene glycol (ZnBG). Inhibition of ERK1/2 using UO126 or PD98059 reduced but did not abolish OA-NO2-induced HIF-1α upregulation, suggesting that OA-NO2/HO-1-initiated HIF-1α induction is partially dependent on ERK1/2 activity. In addition, OA-NO2 enhanced endothelial intracellular Ca2+, an effect that was inhibited by the HIF-1α inhibitor, YC-1, and by HIF-1α siRNA. These results implicate the involvement of HIF-1α. Experiments using the Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) inhibitor STO-609, the selective CaMKII inhibitor KN-93, and an isoform-specific siRNA demonstrated that OA-NO2-induced AMPK phosphorylation was dependent on CaMKKβ. Together, these results demonstrate that OA-NO2 activates AMPK in endothelial cells via an HO-1–dependent mechanism that increases HIF-1α protein expression and Ca2+/CaMKKβ activation.
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