Blockade of endogenous cytokines mitigates neointimal formation in obese Zucker rats
Blockade of endogenous cytokines mitigates neointimal formation in obese Zucker rats
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DOI：
10.1161/01.cir.0000158482.83179.db
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发表时间：
2005-03-22
期刊：
影响因子：
37.8
通讯作者：
Hirata, Y
中科院分区：
文献类型：
--
作者：
Takeda, R;Suzuki, E;Hirata, Y
背景-众所周知，糖尿病是血管疾病如动脉粥样硬化和血管成形术后再狭窄的主要危险因素。晚期糖基化终产物（AGE）及其受体（AGEs）与血管疾病，尤其是糖尿病的发生发展密切相关。然而，糖尿病与血管疾病的相关机制尚不清楚。方法和结果：研究内源性细胞因子如肿瘤坏死因子-α在糖尿病血管病变中的作用（TNF-α）和白细胞介素-6在血管疾病的发展和TNF α的表达中的作用，我们使用了semapimod，一种细胞因子产生的药理学抑制剂，并检测其对肥胖Zucker（OZ）大鼠股动脉中新生内膜形成的影响。我们还使用表达TNF-α受体显性失活突变体（AdTNFR Delta C）的腺病毒构建体来阻断内源性TNF-α的作用。与未治疗的OZ大鼠相比，Semapimod显着抑制OZ大鼠的新生内膜形成和表达。通过将一种腺病毒感染到OZ大鼠的股动脉中来克服semapimod对新生内膜形成的这种抑制作用。此外，AdTNFR三角洲C感染显着抑制新生内膜的形成和OZ rats. Conclusions，这些结果表明，内源性细胞因子，特别是TNF-α，在OZ大鼠的股动脉中的表达，有牵连的新生内膜形成，并认为OZ是这些细胞因子对新生内膜形成的影响的调解人。
Background-It is well known that diabetes mellitus is a major risk factor for vascular diseases such as atherosclerosis and restenosis after angioplasty. It has become clear that advanced glycation end products (AGE) and their receptor (RAGE) are implicated in vascular diseases, especially in diabetes mellitus. Nevertheless, the mechanisms by which diabetes mellitus is often associated with vascular diseases remain unclear.Methods and Results-To study the role of endogenous cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 in the development of vascular diseases and in the expression of RAGE, we used semapimod, a pharmacological inhibitor of cytokine production, and examined its effect on neointimal formation in the femoral artery of obese Zucker (OZ) rats. We also used an adenovirus construct expressing a dominant negative mutant of the receptor for TNF-alpha (AdTNFR Delta C) to block the action of endogenous TNF-alpha. Semapimod significantly suppressed neointimal formation and RAGE expression in OZ rats compared with untreated OZ rats. This inhibitory effect of semapimod on neointimal formation was overcome by infection of an adenovirus expressing RAGE into the femoral artery of OZ rats. Furthermore, AdTNFR Delta C infection significantly suppressed neointimal formation and RAGE expression in the femoral artery of OZ rats.Conclusions-These results suggest that endogenous cytokines, especially TNF-alpha, were implicated in neointimal formation in OZ rats and that RAGE was a mediator of the effect of these cytokines on neointimal formation.