权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

A 38-specific inhibitor, FR167653, reduces carotid intimal thickening and ameliorates insulin resistance in balloon-injured diabetic rats

38 特异性抑制剂 FR167653 可减少球囊损伤糖尿病大鼠的颈动脉内膜增厚并改善胰岛素抵抗

基本信息

批准号：
17590913
负责人：
TOMINAGA Makoto
金额：
$ 2.43万
依托单位：
Yamagata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

We have reported that p38 MAP kinase activation can alter a process occurring early in atherosclerosis or the glucose metabolism in diabetes. To explore this possibility, we investigated the effects of FR167653, one of the p38-specific inhibitors, on balloon-injured carotid arterial intimal thickening and glucose metabolism by using male Wistar fatty rats (fa / fa), a genetically established obese-hyperglycemic animal model for Type-II diabetes mellitus, and their littermates (Wistar lean rats, Fa / ?).FR167653 at 30 mg・kg-1・day-1 was orally administered to 12-week-old rats for 21 days, and age-matched rats without the agent were used as the respective controls. Balloon catheterization in the left common carotid artery and the thoracic aorta was performed at day 7, and the artery was removed at day 14 for histological analysis and/or the following immunoblot analysis. Compared with the area ratios of the neointima / media of fatty rats without treatment, those of fatty rats with FR1676 … More 53 and lean rats without treatment were significantly decreased to approximately 45%, while those of lean rats with FR167653 to 30%. The administration of FR167653 also decreased the levels of plasma glucose and systolic blood pressure in fatty rats. Treatment with FR167653 suppressed the levels of phosphorylated extracellular signal-regulated protein kinase 1 / 2, p38 and c-jun NH_2-terminal protein kinase, and even the levels of proliferative cell nuclear antigen (PCNA) in balloon-injured thoracic aortae.In an intragastric glucose load, the levels of both glucose and insulin were significantly decreased when fatty rats were treated with 30 mg・kg^<-1>・day^<-1> of FR167653. In cultured vascular smoot muscle cells (VSMCs) from both fatty and lean rats, insulin-stimulated 2-deoxy-D-glucose uptake were dose-dependently activated by FR167653.In this study, we have established that FR167653 has pleiotropic effects on not only the inhibition of intimal thickening in balloon-injured arteries by attenuating the amount of VSMCs but also the amelioration of insulin resistance. In addition, the suppression of intimal thickening by the agent was more remarkable in diabetic rats. These results provide a new insight into the potential cellular mechanisms in the vasculature whereby the suppression of p38 activity by FR167653 may have clinical benefits and contribute to the prevention of atherosclerosis, such as metabolic syndrome. Less

我们已经报道了p38 MAP激酶激活可以改变动脉粥样硬化或糖尿病葡萄糖代谢早期发生的过程。为了探索这种可能性，我们使用雄性Wistar肥胖大鼠（fa / fa）（一种遗传学上建立的II型糖尿病肥胖高血糖动物模型）及其同窝仔（Wistar瘦大鼠，Fa /？）研究了FR 167653（一种p38特异性抑制剂）对球囊损伤的颈动脉内膜增厚和葡萄糖代谢的影响。以30 mg·kg-1·day-1的FR 167653经口给予12周龄大鼠21天，并将未给予该药物的年龄匹配大鼠用作相应对照。在第7天在左颈总动脉和胸主动脉中进行球囊导管插入术，并在第14天取出动脉用于组织学分析和/或随后的免疫印迹分析。与未经治疗的肥胖大鼠的新生内膜/中膜面积比相比，使用FR 1676的肥胖大鼠的新生内膜/中膜面积比 ...更多信息 53和未治疗的瘦大鼠的体重显著下降至约45%，而使用FR 167653的瘦大鼠的体重下降至30%。FR 167653给药还降低了肥胖大鼠的血糖水平和收缩压。FR 167653可抑制球囊损伤的胸主动脉中磷酸化细胞外信号调节蛋白激酶1 / 2、p38和c-jun NH_2-末端蛋白激酶的水平，甚至抑制增殖细胞核抗原（PCNA）的水平<-1><-1>。在培养的肥胖和瘦大鼠血管平滑肌细胞（VSMCs）中，FR 167653呈剂量依赖性地激活胰岛素刺激的2-脱氧-D-葡萄糖摄取。在本研究中，我们证实FR 167653不仅通过减少VSMCs的数量来抑制球囊损伤动脉的内膜增厚，而且还具有改善胰岛素抵抗的多效性。此外，药物对糖尿病大鼠内膜增厚的抑制作用更为显著。这些结果为血管系统中潜在的细胞机制提供了新的见解，其中FR 167653对p38活性的抑制可能具有临床益处，并有助于预防动脉粥样硬化，如代谢综合征。少