SMTP-44D has been reported to have anti-oxidative and anti-inflammatory reactions, including reduced expression of
receptor for advanced glycation end products (RAGE) in experimental
diabetic neuropathy. Although activation of RAGE with its
ligands, and
advanced glycation end products (AGEs), play a crucial role in atherosclerotic
cardiovascular disease, a leading cause of death in diabetic patients, it remains unclear whether SMTP-44D could inhibit experimental
atherosclerosis by suppressing the AGEs-RAGE axis. In this study, we investigated the effects of SMTP-44D on
atherosclerotic plaque formation and expression of AGEs in
apolipoprotein-E null (
Apoe-/-) mice. We further studied here whether and how SMTP-44D inhibited foam cell formation of macrophages isolated from
Apoe-/- mice ex vivo. Although administration of SMTP-44D to
Apoe-/- mice did not affect clinical or biochemical parameters, it significantly decreased the surface area of atherosclerotic lesions and reduced the
atheromatous plaque size, macrophage infiltration, and AGEs accumulation in the aortic roots. SMTP-44D bound to immobilized RAGE and subsequently attenuated the interaction of AGEs with RAGE in vitro. Furthermore, foam cell formation evaluated by Dil-
oxidized low-density lipoprotein (
ox-LDL) uptake, and gene expression of RAGE,
cyclin-dependent kinase 5 (Cdk5) and CD36 in macrophages isolated from SMTP-44D-treated
Apoe-/- mice were significantly decreased compared with those from saline-treated mice. Gene expression levels of RAGE and Cdk5 were highly correlated with each other, the latter of which was also positively associated with that of CD36. The present study suggests that SMTP-44D may inhibit
atherosclerotic plaque formation in
Apoe-/- mice partly by blocking the AGEs-RAGE-induced
ox-LDL uptake into macrophages via the suppression of Cdk5-CD36 pathway.