Anti‐atherogenic and anti‐inflammatory properties of glucagon‐like peptide‐1, glucose‐dependent insulinotropic polypepide, and dipeptidyl peptidase‐4 inhibitors in experimental animals

We reported that native incretins, liraglutide and dipeptidyl peptidase‐4 inhibitors (DPP‐4i) all confer an anti‐atherosclerotic effect in apolipoprotein E‐null (Apoe (−/−)) mice. We confirmed the anti‐atherogenic property of incretin‐related agents in the mouse wire injury model, in which the neointimal formation in the femoral artery is remarkably suppressed. Furthermore, we showed that DPP‐4i substantially suppresses plaque formation in coronary arteries with a marked reduction in the accumulation of macrophages in cholesterol‐fed rabbits. DPP‐4i showed an anti‐atherosclerotic effect in Apoe (−/−) mice mainly through the actions of glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypepide. However, the dual incretin receptor antagonists partially attenuated the suppressive effect of DPP‐4i on atherosclerosis in diabetic Apoe (−/−) mice, suggesting an incretin‐independent mechanism. Exendin‐4 and glucose‐dependent insulinotropic polypepide elicited cyclic adenosine monophosphate generation, and suppressed the lipopolysaccharide‐induced gene expression of inflammatory molecules, such as interleukin‐1β, interleukin‐6 and tumor necrosis factor‐α, in U937 human monocytes. This suppressive effect, however, was attenuated by an inhibitor of adenylate cyclase and mimicked by 8‐bromo‐cyclic adenosine monophosphate or forskolin. DPP‐4i substantially suppressed the lipopolysaccharide‐induced expression of inflammatory cytokines without affecting cyclic adenosine monophosphate generation or cell proliferation. DPP‐4i more strongly suppressed the lipopolysaccharide‐induced gene expression of inflammatory molecules than incretins, most likely through inactivation of CD26. Glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypepide suppressed oxidized low‐density lipoprotein‐induced macrophage foam cell formation in a receptor‐dependent manner, which was associated with the downregulation of acyl‐coenzyme A cholesterol acyltransferase‐1 and CD36, as well as the up‐regulation of adenosine triphosphate‐binding cassette transporter A1. Our studies strongly suggest that incretin‐related agents have favorable effects on macrophage‐driven atherosclerosis in experimental animals.