A study on the mechanism of accelerated neointimal formation in a state of insulin resistance

背景众所周知，糖尿病（DM）是动脉粥样硬化和血管成形术后再狭窄等血管疾病的主要危险因素。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，糖尿病与血管疾病相关的机制尚不清楚。方法和结果为了研究内源性细胞因子如肿瘤坏死因子-α（TNF-α）和白细胞介素-6在血管疾病的发生和TNF-α表达中的作用，我们使用了一种细胞因子产生的药理学抑制剂semapimod，并检测了其对肥胖Zucker（OZ）大鼠股动脉新生内膜形成的影响。我们还使用了表达TNF-α受体显性失活突变体（AdTNFRΔC）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，AdTNFRΔC感染可显著抑制OZ大鼠股动脉新生内膜的形成和TGF β 1的表达。结论内源性细胞因子，尤其是TNF-α参与了OZ大鼠血管内膜的形成，TNF-α是这些细胞因子影响血管内膜形成的中介因子。

Background It is well known that diabetes mellitus (DM) 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 DM. However, the mechanisms by which DM is often associated with vascular diseases remain unclear. Methods and Results To study the role of endogenous cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 in the development of vascular diseases and in the expression of RAGE, we used semapimod, a pharmacological inhibitor of cytokines 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-α (AdTNFRΔC) to block the action of endogenous TNF-α. 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, AdTNFRΔC infection significantly suppressed neointimal formation and RAGE expression in the femoral artery of OZ rats. Conclusions These results suggested that endogenous cytokines, especially TNF-α, were implicated in neointimal formation in OZ rats, and that RAGE was a mediator of the effect of these cytokines on neointimal formation.