Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus:: effect of improved metabolic control
Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus:: effect of improved metabolic control
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DOI：
10.1007/s00125-005-1750-2
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发表时间：
2005-06-01
期刊：
影响因子：
8.2
通讯作者：
Mezzetti, A
中科院分区：
文献类型：
--
作者：
Cipollone, F;Chiarelli, F;Mezzetti, A
目的/假设：炎症在糖尿病动脉粥样硬化加速发展中发挥致病作用。可溶性 CD40 配体 (sCD40L) 在糖尿病中增强；然而，sCD40L 与糖尿病动脉粥样硬化加速相关的分子机制仍不清楚。我们测试了这样的假设：sCD40L 可能参与糖尿病的血管并发症，并通过触发单核细胞和内皮细胞 (EC) 的炎症反应来发挥其作用。方法：我们研究了 70 名患者，其中 40 名 2 型糖尿病患者和 30 名 1 型糖尿病患者，有心血管疾病病史或体检阴性，以及 40 名非糖尿病患者和 30 名健康受试者，分别与 2 型糖尿病患者和 1 型糖尿病患者相匹配。测定血浆和血清sCD40L、血浆可溶性细胞间粘附分子-1、可溶性血管细胞粘附分子-1、E-选择素和单核细胞趋化蛋白-1(MCP-1)。用患者或对照血清刺激后，在体外分析粘附分子和 MCP-1 释放、修复 EC 损伤的能力以及单核细胞中 O-2(-) 的生成。结果：2型和1型糖尿病患者的sCD40L水平显着高于对照组。此外，高 sCD40L 与体外粘附分子和 MCP-1 释放、EC 迁移受损以及单核细胞中 O-2(-) 生成增强有关。 12 名 1 型糖尿病患者的代谢控制改善与血浆 sCD40L 降低 37.5% 相关。此外，糖尿病患者升高的 sCD40L 与 HbA(1)c 水平显着相关。结论/解释：糖尿病患者持续高血糖导致 sCD40L 上调，导致 EC 激活和单核细胞募集至动脉壁，可能加速糖尿病动脉粥样硬化的发展。
Aims/hypothesis: Inflammation plays a pathogenic role in the development of accelerated atherosclerosis in diabetes. Soluble CD40 ligand (sCD40L) is enhanced in diabetes; however, the molecular mechanisms linking sCD40L to accelerated atherosclerosis in diabetes are still unclear. We tested the hypothesis that sCD40L may be involved in the vascular complications in diabetes and exerts its effect by triggering inflammatory reactions on mononuclear and endothelial cells (ECs). Methods: We studied 70 patients, 40 with type 2 and 30 with type 1 diabetes, with a history or physical examination negative for cardiovascular disease, and 40 non-diabetic and 30 healthy subjects, matched with the type 2 and type 1 diabetic patients, respectively. Plasma and serum sCD40L, and plasma soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, E-selectin and monocyte chemo-attractant protein-1 (MCP-1) were measured. Adhesion molecules and MCP-1 release, the ability to repair an injury in ECs, and O-2(-) generation in monocytes were analysed in vitro after stimulation with serum from patients or controls. Results: Type 2 and type 1 diabetic patients had significantly higher sCD40L levels than controls. Furthermore, high sCD40L was associated with in vitro adhesion molecules and MCP-1 release, impaired migration in ECs and enhanced O-2(-) generation in monocytes. Improved metabolic control was associated with a reduction of plasma sCD40L by 37.5% in 12 type 1 diabetic patients. Furthermore, elevated sCD40L in diabetic patients was significantly correlated with HbA(1)c levels. Conclusions/interpretations: Upregulation of sCD40L as a consequence of persistent hyperglycaemia in diabetic patients results in EC activation and monocyte recruitment to the arterial wall, possibly contributing to accelerated atherosclerosis development in diabetes.