Vasculoprotective effects of anti-tumor necrosis factor-α treatment in aging
Vasculoprotective effects of anti-tumor necrosis factor-α treatment in aging
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DOI：
10.2353/ajpath.2007.060708
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发表时间：
2007-01-01
影响因子：
6
通讯作者：
Ungvari, Zoltan
中科院分区：
文献类型：
--
作者：
Csiszar, Anna;Labinskyy, Nazar;Ungvari, Zoltan
血管老化与肿瘤坏死因子（TNF）-α表达失调有关。TNF-α是血管致动脉粥样硬化表型变化的主要调节因子，并且与内皮功能障碍和细胞凋亡有关。为了检验抗TNF-α治疗在衰老中发挥血管保护作用的假设，用依那西普（1 mg/kg/周，持续4周）治疗老年（29个月大）F344大鼠，依那西普结合TNF-α并使其失活。老年颈动脉对乙酰胆碱的舒张作用降低，内皮细胞O-2（.）产量增加（如二氢乙啶荧光测量所示）。依那西普治疗显著改善了对乙酰胆碱的反应，降低了血管NAD（P）H氧化酶的活性和表达。在老年颈动脉和冠状动脉中，DNA断裂率和caspase 3/7活性增加（表明凋亡细胞死亡率增加），依那西普治疗可减弱。在老年血管中，炎症标记物上调，包括诱导型一氧化氮合酶和细胞间粘附分子-1，而依那西普治疗可降低这些炎症标记物。在年轻动物的颈动脉中，重组TNF-α引起内皮细胞。功能障碍，氧化应激，增加细胞凋亡和促炎基因表达，模仿血管老化的许多症状。因此，我们提出抗TNF-α治疗发挥抗衰老血管保护作用。
Vascular aging is associated with dysregulation of tumor necrosis factor (TNF)-alpha expression. TNF-alpha is a master regulator of vascular proatherogenic phenotypic changes, and it has been linked to endothelial dysfunction and apoptosis. To test the hypothesis that anti-TNF-alpha treatment exerts vasculoprotective effects in aging, aged (29 months old) F344 rats were treated with etanercept (1 mg/kg/week for 4 weeks), which binds and inactivates TNF-a. in aged carotid arteries, relaxations to acetylcholine were decreased, and endothelial O-2(.) production was increased (as shown by dihydroethidine fluorescence measurements). Etanercept treatment significantly improved responses to acetylcholine and decreased vascular NAD(P)H oxidase activity and expression. In aged carotid and coronary arteries, there were increases in DNA fragmentation rate and caspase 3/7 activity (indicating an increased rate of apoptotic cell death), which were attenuated by etanercept treatment. in aged vessels, there was an up-regulation of inflammatory markers, including inducible nitric-oxide synthase and intercellular adhesion molecule-1, which was decreased by etanercept treatment. In carotid arteries of young animals, recombinant TNF-alpha elicited endothelial. dysfunction, oxidative stress, and increased apoptosis and proinflammatory gene expression, mimicking many of the symptoms of vascular aging. Thus, we propose that anti-TNF-alpha treatment exerts anti-aging vasculoprotective effects.