Inhibition of VCAM-1 expression in endothelial cells by CORM-3: The role of the ubiquitin-proteasome system, p38, and mitochondrial respiration
Inhibition of VCAM-1 expression in endothelial cells by CORM-3: The role of the ubiquitin-proteasome system, p38, and mitochondrial respiration
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DOI：
10.1016/j.freeradbiomed.2011.11.035
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发表时间：
2012-02-15
影响因子：
7.4
通讯作者：
Rafat, Neysan
中科院分区：
文献类型：
--
作者：
Bergstraesser, Claudia;Hoeger, Simone;Rafat, Neysan
一氧化碳（CO）消除了内皮细胞中TNF-α介导的炎症反应，但其潜在机制仍然是难以捉摸的。我们以前已经表明，CO释放分子-3（CORM-3）的抗炎作用并不完全通过NF-κ B通路的失活介导。在这项研究中，我们试图探索CORM-3下调TNF-α刺激的HUVECs上VCAM-1表达的其他潜在机制。通过全基因组基因表达谱和途径分析，我们研究了CORM-3抗炎作用的特定途径的相关性。在CORM-3刺激的HUVECs中，发现蛋白酶体和卟啉途径中涉及的基因的表达发生了显着变化。虽然蛋白酶体活性增加CORM-3，蛋白酶体抑制剂没有取消CORM-3的效果。同样，血红素加氧酶-1抑制剂并没有消除CORM-3下调VCAM-1表达的能力。有趣的是，CORM-3抑制MAPK p38，p38抑制剂SB 203580下调VCAM-1的表达。然而，下调VCAM-1的CORM-3只发生在浓度，部分抑制ATP的生产和叠氮化钠和寡霉素的CORM-3在这方面的效果。我们的研究结果表明，CORM-3诱导的VCAM-1下调介导的p38抑制和线粒体呼吸，而泛素-蛋白酶体系统似乎没有参与。(C)2011 Elsevier Inc. All rights reserved.
Carbon monoxide (CO) abrogates TNF-alpha-mediated inflammatory responses in endothelial cells, yet the underlying mechanism thereof is still elusive. We have previously shown that the anti-inflammatory effect of CO-releasing molecule-3 (CORM-3) is not completely mediated via deactivation of the NF-kappa B pathway. In this study, we sought to explore other potential mechanisms by which CORM-3 downregulates VCAM-1 expression on TNF-alpha-stimulated HUVECs. By genome-wide gene expression profiling and pathway analysis we studied the relevance of particular pathways for the anti-inflammatory effect of CORM-3. In CORM-3-stimulated HUVECs significant changes in expression were found for genes implicated in the proteasome and porphyrin pathways. Although proteasome activities were increased by CORM-3, proteasome inhibitors did not abolish the effect of CORM-3. Likewise, heme oxygenase-1 inhibitors did not abrogate the ability of CORM-3 to downregulate VCAM-1 expression. Interestingly, CORM-3 inhibited MAPK p38, and the p38 inhibitor SB203580 downregulated VCAM-1 expression. However, downregulation of VCAM-1 by CORM-3 occurred only at concentrations that partly inhibit ATP production and sodium azide and oligomycin paralleled the effect of CORM-3 in this regard. Our results indicate that CORM-3-induced downregulation of VCAM-1 is mediated via p38 inhibition and mitochondrial respiration, whereas the ubiquitin-proteasome system seems not to be involved. (C) 2011 Elsevier Inc. All rights reserved.