Ac-SDKP suppresses TNF-α-induced ICAM-1 expression in endothelial cells via inhibition of IκB kinase and NF-κB activation
Ac-SDKP suppresses TNF-α-induced ICAM-1 expression in endothelial cells via inhibition of IκB kinase and NF-κB activation
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DOI：
10.1152/ajpheart.00252.2015
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发表时间：
2016-05-01
影响因子：
4.8
通讯作者：
Carretero, Oscar A.
中科院分区：
文献类型：
--
作者：
Zhu, Liping;Yang, Xiao-Ping;Carretero, Oscar A.
N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases. We previously showed that, in angiotensin II-induced hypertension, Ac-SDKP decreased the activation of nuclear transcription factor NF-kappa B, whereas, in experimental autoimmune myocarditis and hypertension animal models, it also reduced the expression of endothelial leukocyte adhesion molecule ICAM-1. However, the mechanisms by which Ac-SDKP downregulated ICAM-1 expression are still unclear. TNF-alpha is a proinflammatory cytokine that induces ICAM-1 expression in various cell types via TNF receptor 1 and activation of the classical NF-kappa B pathway. We hypothesized that in endothelial cells Ac-SDKP suppresses TNF-alpha-induced ICAM-1 expression by decreasing IKK phosphorylation that as a consequence leads to a decrease of I kappa B phosphorylation and NF-kappa B activation. To test this hypothesis, human coronary artery endothelial cells were treated with Ac-SDKP and then stimulated with TNF-alpha. We found that TNF-alpha-induced ICAM-1 expression was significantly decreased by Ac-SDKP in a dose-dependent manner. Ac-SDKP also decreased TNF-alpha-induced NF-kappa B translocation from cytosol to nucleus, as assessed by electrophoretic mobility shift assay, which correlated with a decrease in I kappa B phosphorylation. In addition, we found that Ac-SDKP decreased TNF-alpha-induced IKK phosphorylation and IKK-beta expression. However, Ac-SDKP had no effect on TNF-alpha-induced phosphorylation of p38 MAP kinase or ERK. Thus we conclude that Ac-SDKP inhibition of TNF-alpha activation of canonical, i.e., IKK-beta-dependent, NF-kappa B pathway and subsequent decrease in ICAM-1 expression is achieved via inhibition of IKK-beta
