DPP-4 (CD26) Inhibitor Alogliptin Inhibits Atherosclerosis in Diabetic Apolipoprotein E–Deficient Mice

Abstract

Dipeptidyl peptidase-4 (DPP-4 or CD26) inhibitors, a new class of anti-diabetic compounds, are effective in treatment of hyperglycemia. Since atherosclerosis-related cardiovascular diseases are the major complications of diabetes, it is important to determine the effect of DPP-4 inhibitors on atherosclerosis. In this study, nondiabetic and diabetic apolipoprotein E (apoE)-deficient mice were treated with DPP-4 inhibitor alogliptin for 24 weeks and atherosclerotic lesions in aortic origins were examined. Results showed that diabetes significantly increased atherosclerotic lesions, but alogliptin treatment reduced atherosclerotic lesions in diabetic mice. Metabolic studies showed that diabetes increased plasma glucose and alogliptin treatment reduced glucose. Furthermore, immunohistochemistry study showed that diabetes increased IL-6 and IL-1β protein expression in atherosclerotic plaques, but alogliptin treatment attenuated diabetes-augmented IL-6 and IL-1β expression. In consistence with the observations from the mouse models, our in vitro studies showed that alogliptin inhibited toll-like receptor (TLR)4-mediated upregulation of IL-6, IL-1β, and other proinflammatory cytokines by mononuclear cells. Taken together, our findings showed that alogliptin inhibited atherosclerosis in diabetic apoE-deficient mice and the actions of alogliptin on both glucose and inflammation may contribute to the inhibition.

A Dipeptidyl Peptidase-4 Inhibitor but not Incretins Suppresses Abdominal Aortic Aneurysms in Angiotensin II-Infused Apolipoprotein E-Null Mice

“…To obtain further insight into the role of incretins in the effects of DPP- activity. It has also been reported that a DPP-4I inhibited toll-like receptor 4-mediated extracellular signalregulated kinase (ERK) activation and ERK-dependent MMP expression in monocytes 31,38) . ERK activation is known to be involved in Ang -induced AAA formation 39) .…”

“…Moreover, genetic depletion of IL-1 and the IL-1 receptor as well as pharmacological inhibition of the IL-1 receptor suppressed AAA formation in mice 30) . Ta et al reported that a DPP-4I suppressed IL-1 expression in cultured human monocytes 31) . Collectively, these results indicate that decreased IL-1 expression can in part explain the protective effect of DPP-4I against AAA formation.…”

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

“…DPP‐4 inhibitors are widely used antidiabetic drugs; however, the anti‐inflammatory effects against cardiovascular diseases, including myocardial infarction,16 arthrosclerosis,7, 17 and abdominal aortic aneurysms,8 have been reported in animal models. Anagliptin, a DPP‐4 inhibitor, also has anti‐inflammatory effects, and according to phase 3 clinical trials, anagliptin treatment improves serum lipid profiles 18…”

Rationale, Design, and Baseline Characteristics of a Trial for the Prevention of Diabetic Atherosclerosis Using a DPP-4 Inhibitor: The Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A)

“…Furthermore, in vivo and in vitro studies have shown that alogliptin exerts anti-atherosclerotic effects in mice and reduces inflammation via its inhibition of monocyte activation/chemotaxis 18) . Another study also showed that alogliptin inhibited atherosclerosis in diabetic apoE-deficient mice by inhibiting the upregulation of proinflammatory cytokines by mononuclear cells 19) . Therefore, alogliptin is expected to reduce the risk of cardiovascular disease.…”