Brodsky Sergey V, Gealekman Olga, Chen Jun, Zhang Fan, Togashi Nobuhiko, Crabtree Mark, Gross Steven S, Nasjletti Alberto, Goligorsky Michael S
Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
Circ Res. 2004 Feb 20;94(3):377-84. doi: 10.1161/01.RES.0000111802.09964.EF. Epub 2003 Dec 11.
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.
尽管代谢综合征患者心血管系统的动脉粥样硬化加速和过早衰老已为人所知，但其发生机制和潜在的治疗干预措施仍未解决。我们之前的研究表明，晚期糖基化终产物参与了过早衰老的发生，而过氧亚硝酸盐清除剂依布硒仑可预防这种衰老。因此，我们研究了依布硒仑对代谢综合征模型——Zucker糖尿病大鼠（ZDF）的内皮细胞衰老和血管病变的影响。依布硒仑降低了ZDF大鼠中3-硝基酪氨酸修饰蛋白的丰度。依布硒仑可预防22周龄ZDF大鼠衰老内皮细胞数量增加6倍。从8周到22周给予依布硒仑时，由乙酰胆碱诱导的血管舒张、一氧化氮产生、血管生成能力和循环微粒数量共同判断的血管病变发展几乎完全得到预防，而当治疗间隔为13周到22周时，血管病变部分得到逆转。总之，内皮细胞过早衰老在ZDF大鼠中逐渐加剧，并与严重血管病变的体征相关。此外，通过控制硝基酪氨酸形成的减少来预防血管内皮过早衰老与血管病变的改善在时间上相关，这支持了内皮细胞过早衰老在糖尿病大血管病变中具有致病作用的观点。
