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

内皮功能障碍在糖尿病（DM）中经常观察到。然而，糖尿病内皮功能障碍的详细机制仍不清楚。据报道，在DM中，脂肪细胞释放的细胞因子如TNF-α和IL-6增加，并诱导血管炎症。在这项研究中，我们研究了内源性细胞因子在糖尿病内皮功能障碍中的作用，使用semapimod（Sem），内源性细胞因子释放的抑制剂。将雄性糖尿病Zucker大鼠（12周）分为瘦（LZ）、肥胖（OZ）和Sem（5 mg/kg/天）治疗的肥胖大鼠（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）的内皮依赖性舒张反应。此外，通过Western印迹分析检测用10 μ L AM刺激15分钟的胸主动脉的Akt磷酸化（p-Akt）的诱导<-7>。OZ大鼠的收缩压、血糖和甘油三酯较高，而Sem治疗对这些参数没有影响。OZ组大鼠血清CRP水平高于LZ组，Sem组血清CRP水平明显低于LZ组。OZ大鼠各组织中TNF-α、IL-1β和IL-6含量显著高于LZ大鼠，而OZ/Sem大鼠抑制了这些增量。ACh和AM的内皮依赖性血管舒张作用在OZ大鼠中显著减弱，并通过Sem治疗得到改善。腹腔注射TNF-α可明显抑制ACh引起的LZ大鼠胸主动脉舒张反应。与LZ大鼠相比，OZ大鼠胸主动脉AM诱导的p-Akt和cGMP产生显著减少。然而，通过Sem治疗，其恢复。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.