Prevention and reversal of premature endothelial cell senescence and vasculopathy in obesity-induced diabetes by ebselen
Prevention and reversal of premature endothelial cell senescence and vasculopathy in obesity-induced diabetes by ebselen
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DOI：
10.1161/01.res.0000111802.09964.ef
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发表时间：
2004-02-20
影响因子：
20.1
通讯作者：
Goligorsky, MS
中科院分区：
文献类型：
--
作者：
Brodsky, SV;Gealekman, O;Goligorsky, MS
虽然代谢综合征患者的动脉粥样硬化加速和心血管系统过早老化已被认识到，但其发生机制和潜在的治疗干预措施仍未解决。我们以前的研究表明，晚期糖基化终末产物与早衰的发生有关，过氧亚硝酸盐清除剂ebselen可以预防。因此，研究依布硒对代谢综合征模型--Zucker糖尿病大鼠(ZDF)血管内皮细胞衰老和血管病变的影响。依布硒降低ZDF大鼠3-硝基酪氨酸修饰蛋白的丰度。22周龄ZDF的衰老内皮细胞数量增加了6倍，Ebselen可以阻止。以乙酰胆碱诱导的血管松弛、NO生成、血管生成能力和循环微粒数量为指标共同判断的血管病变的发生，在给药8~22周时几乎完全阻止，在治疗间隔13~22周时部分逆转。综上所述，ZDF大鼠血管内皮细胞的早衰逐渐猖獗，并与严重血管病变的征兆有关。此外，通过控制硝基酪氨酸生成的减少来预防血管内皮细胞的早衰与血管病变的改善有关，这支持了内皮细胞早衰在糖尿病大血管病变中的发病作用的观点。
Although the accelerated atherosclerosis and premature aging of the cardiovascular system in patients with metabolic syndrome have been appreciated, the mechanisms of their development and potential therapeutic interventions remain unresolved. Our previous studies implicated advanced glycosylation end products in development of premature senescence preventable with a peroxynitrite scavenger, ebselen. Therefore, the effect of ebselen on endothelial senescence and vasculopathy in a model of metabolic syndrome-Zucker diabetic rats (ZDF)-was investigated. Ebselen decreased the abundance of 3-nitrotyrosine-modified proteins in ZDF rats. A 6-fold increase in the number of senescent endothelial cells in 22-week-old ZDF was prevented by ebselen. Development of vasculopathy, as collectively judged by the acetylcholine-induced vasorelaxation, NO production, angiogenic competence, and number of circulating microparticles, was almost completely prevented when ebselen was administered from 8 to 22 weeks and partially reversed when the treatment interval was 13 to 22 weeks. In conclusion, premature senescence of endothelial cells is progressively rampant in ZDF rats and is associated with the signs of severe vasculopathy. In addition, prevention of premature senescence of vascular endothelium through controlled decrease in nitrotyrosine formation was chronologically associated with the amelioration of vasculopathy, lending support to the idea of the pathogenetic role of premature senescence of endothelial cells in diabetic macrovasculopathy.