Sitagliptin inhibits vascular inflammation via the SIRT6-dependent signaling pathway

Abstract Sitagliptin has recently been shown to inhibit inflammatory response in cardiovascular disease. Sirtuin6 (SIRT6), a NAD+-dependent class III histone deacetylase, participates in the regulation of cellular inflammation. We hypothesized that sitagliptin could attenuate vascular inflammation via modulation of SIRT6 pathway. It was found that sitagliptin decreased the expression of monocyte chemotactic protein-1 (MCP-1), interleukin (IL)-6 and IL-1β, but up-regulated SIRT6 expression, both in mice and in TNF-α-stimulated endothelial cells. Moreover, knockdown of SIRT6 reversed the inhibitory effect of sitagliptin on MCP-1, IL-6 and IL-1β expression. Further study revealed that sitagliptin also decreased the expression of MCP-1, IL-6 and IL-1β partly through suppression of reactive oxygen species (ROS). In vivo, hypercholesterolemia in mice was induced by intraperitoneal administration of poloxamer 407 for 1 month. Hyperlipidemia-induced production of MCP-1, IL-6 and IL-1β was significantly suppressed in the sitagliptin-supplemented animals, but the effect of was abolished by SIRT6 knockout in endothelium. These results indicate that sitagliptin protects against vascular inflammation via the SIRT6/ROS-dependent signaling pathway.