Studies on visualization of arteriosclerotic lesion using vascular cell-derived vasoactive substances

糖尿病(DM)患者常可观察到内皮功能障碍。然而，糖尿病血管内皮细胞功能障碍的详细机制仍不清楚。据报道，在糖尿病中，脂肪细胞释放的细胞因子如肿瘤坏死因子-α和白介素6等增加，并引发血管炎症。在这项研究中，我们使用内源性细胞因子释放的抑制剂赛马普莫特(Semapimod，Sem)来研究内源性细胞因子在糖尿病血管内皮细胞功能障碍中的作用。雄性糖尿病Zucker大鼠(12周龄)分为瘦(LZ)、肥胖(OZ)和Sem(5 mg/kg/d)治疗肥胖大鼠(OZ/Sem)。治疗4周后，检测胸主动脉对乙酰胆碱(ACh)和肾上腺髓质素(AM)的内皮依赖性血管扩张反应。此外，用Western印迹法检测AM 10^~(-7)&gt~(-1)刺激15min后胸主动脉Akt磷酸化(p-Akt)的诱导。OZ大鼠的收缩压、血糖和甘油三酯较高，Sem治疗对这些参数没有影响。OZ大鼠血清CRP水平明显高于LZ大鼠，Sem显著降低其水平。OZ大鼠各组织中肿瘤坏死因子-α、IL-1β和IL-6的含量显著高于LZ大鼠，而OZ/Sem大鼠这些增加受到抑制。ACh和AM对OZ大鼠的内皮依赖性血管扩张作用明显减弱，Sem可改善其作用。LZ大鼠腹腔注射肿瘤坏死因子-α可显著降低ACh诱发的胸主动脉扩张反应。AM诱导的胸主动脉p-Akt和cGMP的产生在OZ大鼠显著低于LZ大鼠。但经Sem处理后恢复正常。在糖尿病中，内源性细胞因子在内皮功能障碍中起重要作用，抑制这些细胞因子的释放可能会改善内皮功能障碍。

Endothelial dysfunction is frequently observed in diabetes (DM). However, the detailed mechanism for endothelial dysfunction in DM is still unclear. In DM, it has been reported that cytokines release from adipocytes such as TNF-α and IL-6 is augmented and that they induce vascular inflammation. In this study we study the role of endogenous cytokines in endothelial dysfunction in DM with using semapimod (Sem), an inhibitor of endogenous cytokines release. Male diabetic Zucker rats (12 weeks) were divided into lean (LZ), obese (OZ), and Sem (5mg/kg/day)-treated obese rats (OZ/Sem). After 4 weeks of treatment, endothelium dependent vasodilatory responses of thoracic aorta to acetylcholine (ACh) and adrenomedullin (AM) were examined. Furthermore, induction of Akt phosphorylation (p-Akt) of thoracic aorta which was stimulated with 10^<-7> of AM for 15 min was examined by Western blot analysis. Systolic blood pressure, blood glucose, and triglyceride were higher in OZ rats and Sem treatment had no effect on these parameters. Serum CRP level of OZ rats was higher compared to LZ rats and Sem significantly reduced its level. TNF-α, IL-1β, and IL-6 contents in various tissues were significantly greater in OZ rats than in LZ rats, whereas these increments were suppressed in OZ/Sem rats. Endothelium-dependent vasodilation by ACh and AM was significantly attenuated in OZ rats, and was improved by Sem treatment. Intraperitoneal administration of TNF-α markedly reduced ACh-evoked vasodilation in thoracic aorta of LZ rats. AM-induced p-Akt and cGMP production of thoracic aorta were significantly less in OZ rats compared to LZ rats. However, it was recovered by Sem treatment. In DM, endogenous cytokines play an important role in endothelial dysfunction and inhibition of these cytokines release may improve endothelial dysfunction.