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.
['Hirano|Tsutomu|T|', 'Mori|Yusaku|Y|']
D000818:Animals D000893:Anti-Inflammatory Agents D001057:Apolipoproteins E D050197:Atherosclerosis D023903:Coronary Restenosis D054873:Dipeptidyl-Peptidase IV Inhibitors D004195:Disease Models, Animal D005487:Foam Cells D005749:Gastric Inhibitory Polypeptide D052216:Glucagon-Like Peptide 1 D006801:Humans D006965:Hyperplasia D054795:Incretins D007249:Inflammation D018836:Inflammation Mediators D000069450:Liraglutide D008264:Macrophages D051379:Mice D018345:Mice, Knockout D009000:Monocytes
Incretins Atherosclerosis Vascular inflammation