Blockade of endogenous proinflammatory cytokines ameliorates endothelial dysfunction in obese Zucker rats
Blockade of endogenous proinflammatory cytokines ameliorates endothelial dysfunction in obese Zucker rats
复制标题
DOI：
10.1291/hypres.31.737
复制
发表时间：
2008-04-01
影响因子：
5.4
通讯作者：
Hirata, Yasunobu
中科院分区：
文献类型：
--
作者：
Nishimatsu, Hiroaki;Suzuki, Etsu;Hirata, Yasunobu
为了研究内源性促炎细胞因子在糖尿病血管内皮功能障碍中的作用，我们给肥胖的Zucker(OZ)大鼠应用促炎细胞因子产生的抑制剂赛马普莫特，观察其对内皮依赖性血管松弛的影响。与对照组瘦Zucker大鼠相比，OZ大鼠由乙酰胆碱和肾上腺髓质素(AM)诱导的内皮依赖性血管松弛作用明显减弱。赛马普莫特能显著恢复OZ大鼠的内皮依赖性血管松弛。Semapimod的这种作用与降低血清肿瘤坏死因子-α(TNF-α)、白介素6和C-反应蛋白浓度以及恢复AM诱导的Akt磷酸化和cGMP产生密切相关。此外，急性给予肿瘤坏死因子-a显著抑制内皮依赖的血管松弛和AM诱导的cGMP的产生。这些结果提示内源性促炎细胞因子，尤其是肿瘤坏死因子-α参与了糖尿病血管内皮细胞功能障碍，并表明阻断这些细胞因子将是抑制血管炎症进展的一种有前途的策略。
To study the role of endogenous proinflammatory cytokines in endothelial dysfunction in diabetes, we administered semapimod, an inhibitor of proinflammatory cytokine production, to obese Zucker (OZ) rats, and examined its effect on endothelium-dependent vasorelaxation. Endothelium-dependent vasorelaxation induced by acetylcholine and adrenomedullin (AM) was significantly reduced in OZ rats compared to a control group of lean Zucker rats. Semapimod significantly restored endothelium-dependent vasorelaxation in OZ rats. This effect of semapimod was well correlated with the reduction in the serum concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-6, and C-reactive protein, as well as with the recovery of AM-induced Akt phosphorylation and cGMP production. Furthermore, acute administration of TNF-a significantly suppressed endothelium-dependent vasorelaxation and AM-induced cGMP production. These results implicate endogenous proinflammatory cytokines, especially TNF-alpha, in endothelial dysfunction in diabetes, and indicate that blockade of these cytokines will be a promising strategy for inhibiting the progression of vascular inflammation.