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

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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.