Anagliptin, a DPP-4 Inhibitor, Suppresses Proliferation of Vascular Smooth Muscles and Monocyte Inflammatory Reaction and Attenuates Atherosclerosis in Male apo E-Deficient Mice

Abstract

Dipeptyl peptidase-4 (DPP-4) inhibitors modulate the progression of atherosclerosis. To gain insights into their mechanism of action, 9-wk-old male apolipoprotein E (apoE)-deficient mice were fed a DPP-4 inhibitor, anagliptin-containing diet. The effects of anagliptin were investigated in, a monocyte cell line, human THP-1 cells, and rat smooth muscle cells (SMCs). Treatment with anagliptin for 16 wk significantly reduced accumulation of monocytes and macrophages in the vascular wall, SMC content in plaque areas, and oil red O-stained area around the aortic valve without affecting glucose tolerance or body weight. Serum DPP-4 concentrations were significantly higher in apoE-deficient mice than control mice, and the levels increased with aging, suggesting the involvement of DPP-4 in the progression of atherosclerosis. Indeed, soluble DPP-4 augmented cultured SMC proliferation, and anagliptin suppressed the proliferation by inhibiting ERK phosphorylation. In THP-1 cells, anagliptin reduced lipopolysaccharide-induced TNF-α production with inhibiting ERK phosphorylation and nuclear translocation of nuclear factor-κB. Quantitative analysis also showed that anagliptin reduced the area of atherosclerotic lesion in apoE-deficient mice. These results indicated that the anti-atherosclerotic effect of anagliptin is mediated, at least in part, through its direct inhibition of SMC proliferation and inflammatory reaction of monocytes.

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

“…For instance, administering antagonists of GLP‐1 and GIP incompletely blocks the antiatherosclerotic effects of vildagliptin in diabetic, apolipoprotein E–deficient mice 25. Anagliptin suppresses lipopolysaccharide‐induced production of proinflammatory cytokines in human and mouse macrophage‐like cells by inhibiting the NF‐κB and MAPK pathways 7, 26. In this study, we demonstrated that the anti‐inflammatory action of anagliptin in macrophages was at least partly independent of GLP‐1 receptor signaling.…”

“…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…”

“…Notably, the expression of DPP‐4 increases during inflammation, suggesting that, in addition to its function in blood glucose homeostasis, DPP‐4 participates in the pathogenesis of inflammatory diseases. Accordingly, the DPP‐4 inhibitor anagliptin prevents the progression of atherosclerosis7 and abdominal aortic aneurysms8 by mitigating macrophage activation and accumulation. During the growth of IAs, macrophage infiltration disrupts the extracellular matrix through the secretion of macrophage‐derived matrix metalloproteinases including MMP‐2 and MMP‐9 9.…”

DPP4 Inhibition Ameliorates Cardiac Function by Blocking the Cleavage of HMGB1 in Diabetic Mice After Myocardial Infarction

“…The dose of anagliptin was determined from previous reports. [22][23][24] In order to determine whether the dose of anagliptin (300 mg/kg/day) was adequate to inhibit DPP4 activity, DPP4 activity was measured as described in the next section, and we found DPP4 activity in this study was inhibited in nearly equal level compared with those of previous experiments (80-90% inhibition of DPP4 activity). 22,25,26) Echocardiography was performed in order to evaluate the cardiac function of the mice at day 52 (four weeks after MI induction).…”

Impact of incretin-related agents on endothelial cell function

“…However, the precise signaling of GLP-1 analogues has not been fully determined in humans. 36 Additionally, pancreatic beta-cells are known to be sensitive to oxidative stresses that result from relatively low expression levels of anti-oxidant enzymes, such 45 . Despite these many favorable mechanisms, many clinical trials using DPP-4 inhibitors failed to show their superiority to placebo in CVD outcomes.…”