Antagonistic effect of TNF-alpha and insulin on uncoupling protein 2 (UCP-2) expression and vascular damage.
Antagonistic effect of TNF-alpha and insulin on uncoupling protein 2 (UCP-2) expression and vascular damage.
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TNF-α和胰岛素对解偶联蛋白2（UCP-2）表达和血管损伤的拮抗作用。
DOI：
10.1186/s12933-014-0108-9
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发表时间：
2014-07-31
影响因子：
9.3
通讯作者：
Benito M
中科院分区：
文献类型：
--
作者：
Gómez-Hernández A;Perdomo L;de las Heras N;Beneit N;Escribano O;Otero YF;Guillén C;Díaz-Castroverde S;Gozalbo-López B;Cachofeiro V;Lahera V;Benito M
据报道，血管系统中UCP-2的表达增加可以防止活性氧产生增加的患者中动脉粥样硬化的发展，如糖尿病、肥胖症或高血压。因此，更好地了解UCP-2的调节可以改善动脉粥样硬化过程。然而，TNF-α或胰岛素调节UCP-2在血管壁中的作用完全未知。在这种情况下，我们建议研究新的分子机制，以帮助解释是否中度高胰岛素血症或降低TNF-α水平可能对UCP-2表达水平介导的血管损伤具有保护作用。我们分析了在TNF-α存在或不存在的情况下胰岛素或油酸对小鼠内皮细胞和血管平滑肌细胞中UCP-2表达的影响。在这一步，我们想知道一些体外研究的机制是否与体内有关。我们使用了以下实验模型：ApoE−/−小鼠在西式饮食下喂养2、6、12或18周，BATIRKO小鼠在高脂饮食下喂养16周，52周龄的BATIRKO小鼠未接受抗TNF-α抗体预处理。首先，我们发现TNF-α预处理降低了胰岛素诱导的血管细胞UCP-2的表达。其次，我们观察到ApoE−/−小鼠主动脉中UCP-2水平逐渐降低，脂质贮库和病变面积增加。在体内，我们还观察到中度高胰岛素血症肥胖BATIRKO小鼠主动脉内TNF-α和ROS水平较低，UCP-2表达水平升高，脂质蓄积较低，血管功能障碍和大血管损伤。我们还观察到，抗TNF-α抗体预处理损害了主动脉内UCP-2表达的丧失，并减轻了在52周龄BATIRKO小鼠中观察到的血管损伤。最后，我们观察到用iNOS抑制剂预处理可以阻止TNF-α诱导的血管细胞中UCP-2的减少。此外，在UCP-2水平较低和TNF-α水平较高的小鼠的主动脉中，iNOS水平增加。我们的数据表明，中度高胰岛素血症对胰岛素抵抗或降低主动脉内TNF-α水平的反应可减轻血管损伤，这种保护作用是通过iNOS介导的UCP-2表达水平。本文的在线版本（doi：10.1186/s12933-014-0108-9）包含补充材料，可供授权用户使用。
It has been reported that increased expression of UCP-2 in the vasculature may prevent the development of atherosclerosis in patients with increased production of reactive oxygen species, as in the diabetes, obesity or hypertension. Thus, a greater understanding in the modulation of UCP-2 could improve the atherosclerotic process. However, the effect of TNF-α or insulin modulating UCP-2 in the vascular wall is completely unknown. In this context, we propose to study new molecular mechanisms that help to explain whether the moderate hyperinsulinemia or lowering TNF-α levels might have a protective role against vascular damage mediated by UCP-2 expression levels. We analyzed the effect of insulin or oleic acid in presence or not of TNF-α on UCP-2 expression in murine endothelial and vascular smooth muscle cells. At this step, we wondered if some mechanisms studied in vitro could be of any relevance in vivo. We used the following experimental models: ApoE−/− mice under Western type diet for 2, 6, 12 or 18 weeks, BATIRKO mice under high-fat diet for 16 weeks and 52-week-old BATIRKO mice with o without anti-TNF-α antibody pre-treatment. Firstly, we found that TNF-α pre-treatment reduced UCP-2 expression induced by insulin in vascular cells. Secondly, we observed a progressive reduction of UCP-2 levels together with an increase of lipid depots and lesion area in aorta from ApoE−/− mice. In vivo, we also observed that moderate hyperinsulinemic obese BATIRKO mice have lower TNF-α and ROS levels and increased UCP-2 expression levels within the aorta, lower lipid accumulation, vascular dysfunction and macrovascular damage. We also observed that the anti-TNF-α antibody pre-treatment impaired the loss of UCP-2 expression within the aorta and relieved vascular damage observed in 52-week-old BATIRKO mice. Finally, we observed that the pretreatment with iNOS inhibitor prevented UCP-2 reduction induced by TNF-α in vascular cells. Moreover, iNOS levels are augmented in aorta from mice with lower UCP-2 levels and higher TNF-α levels. Our data suggest that moderate hyperinsulinemia in response to insulin resistance or lowering of TNF-α levels within the aorta attenuates vascular damage, this protective effect being mediated by UCP-2 expression levels through iNOS. The online version of this article (doi:10.1186/s12933-014-0108-9) contains supplementary material, which is available to authorized users.
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影响因子：
8.2
作者：
Dalgaard, LT;Pedersen, O
通讯作者：
Pedersen, O
影响因子：
4.1
作者：
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