Nitric Oxide-Induced Activation of the AMP-Activated Protein Kinase α2 Subunit Attenuates IκB Kinase Activity and Inflammatory Responses in Endothelial Cells

被引:77
作者
Bess, Elke [1 ]
Fisslthaler, Beate [1 ]
Froemel, Timo [1 ]
Fleming, Ingrid [1 ]
机构
[1] Goethe Univ Frankfurt, Ctr Mol Med, Inst Vasc Signalling, Frankfurt, Germany
来源
PLOS ONE | 2011年 / 6卷 / 06期
关键词
STRESS-INDUCED ACTIVATION; SHEAR-STRESS; GENE-EXPRESSION; ADIPONECTIN; PHOSPHORYLATION; BRADYKININ; INDUCTION; ISOFORM; ENOS;
D O I
10.1371/journal.pone.0020848
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: In endothelial cells, activation of the AMP-activated protein kinase (AMPK) has been linked with anti-inflammatory actions but the events downstream of kinase activation are not well understood. Here, we addressed the effects of AMPK activation/deletion on the activation of NF kappa B and determined whether the AMPK could contribute to the anti-inflammatory actions of nitric oxide (NO). Methodology/Principal Findings: Overexpression of a dominant negative AMPK alpha 2 mutant in tumor necrosis factor-alpha-stimulated human endothelial cells resulted in increased NF kappa B activity, E-selectin expression and monocyte adhesion. In endothelial cells from AMPK alpha 2(-/-) mice the interleukin (IL)-1 beta induced expression of E-selectin was significantly increased. DETA-NO activated the AMPK and attenuated NF kappa B activation/E-selectin expression, effects not observed in human endothelial cells in the presence of the dominant negative AMPK, or in endothelial cells from AMPK alpha 2(-/-) mice. Mechanistically, overexpression of constitutively active AMPK decreased the phosphorylation of I kappa B and p65, indicating a link between AMPK and the I kappa B kinase (IKK). Indeed, IKK (more specifically residues Ser177 and Ser181) was found to be a direct substrate of AMPK alpha 2 in vitro. The hyper-phosphorylation of the IKK, which is known to result in its inhibition, was also apparent in endothelial cells from AMPK alpha 2(+/+) versus AMPK alpha 2(-/-) mice. Conclusions: These results demonstrate that the IKK is a direct substrate of AMPK alpha 2 and that its phosphorylation on Ser177 and Ser181 results in the inhibition of the kinase and decreased NF kappa B activation. Moreover, as NO potently activates AMPK in endothelial cells, a portion of the anti-inflammatory effects of NO are mediated by AMPK.
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页数:8
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