Dipeptidyl peptidase-4 inhibitor linagliptin attenuates neointima formation after vascular injury

Abstract

BackgroundRecently, glucagon-like peptide-1 (GLP-1)-based therapy, including dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists, has emerged as one of the most popular anti-diabetic therapies. Furthermore, GLP-1-based therapy has attracted increased attention not only for its glucose-lowering ability, but also for its potential as a tissue-protective therapy. In this study, we investigated the vascular-protective effect of the DPP-4 inhibitor, linagliptin, using vascular smooth muscle cells (VSMCs).MethodsSix-week-old male C57BL/6 mice were divided into control (n =19) and linagliptin (3 mg/kg/day, n =20) treated groups. Endothelial denudation injuries were induced in the femoral artery at 8 weeks of age, followed by evaluation of neointima formation at 12 weeks. To evaluate cell proliferation of rat aortic smooth muscle cells, a bromodeoxyuridine (BrdU) incorporation assay was performed.ResultsLinagliptin treatment reduced vascular injury-induced neointima formation, compared with controls (p <0.05). In these non-diabetic mice, the body weight and blood glucose levels did not change after treatment with linagliptin. Linagliptin caused an approximately 1.5-fold increase in serum active GLP-1 concentration, compared with controls. In addition, the vascular injury-induced increase in the oxidative stress marker, urinary 8-OHdG, was attenuated by linagliptin treatment, though this attenuation was not statistically significant (p =0.064). Moreover, linagliptin did not change the serum stromal cell-derived factor-1α (SDF-1α) or the serum platelet-derived growth factor (PDGF) concentration. However, linagliptin significantly reduced in vitro VSMC proliferation.ConclusionLinagliptin attenuates neointima formation after vascular injury and VSMC proliferation beyond the glucose-lowering effect.

Dipeptidyl peptidase-4 inhibitor linagliptin attenuates neointima formation after vascular injury

“…Further elucidation of DPP-4 substrates is required. Furthermore, Kanasaki et al have recently reported that linagliptin inhibited the endothelial-to-mesenchymal transition in type 1 diabetic mouse kidney, independent of the glucose-lowering effect [37]. This pleiotropic effect could be a potential effect of linagliptin.…”

Mechanisms and pathways of anti‐inflammatory activity of DPP‐4 inhibitors in cardiovascular and renal protection

“…Anti‐inflammatory effects of linagliptin were evidenced in vitro in mouse podocytes . This giptin showed impacts on improvement of vascular dysfunction in vascular tissues in mice and rats . It was reported to attenuate inflammatory processes in myocardium of mice, such as exert renoprotective effects in mice and rats …”

“…This polypeptide decreases MCP‐1 levels through protein kinase A (PKA) signaling what leads to the suppression of ERK and NF‐κB activation . Linagliptin at 3 mg/kg/day orally for 6 weeks reduced oxidative stress and attenuated vascular smooth muscle cells proliferation after vascular injury in mice . It, administered at 10 mg/kg per day orally for 20 weeks, attenuated expression of MCP‐1, VCAM‐1, and NADPH oxidase subunits in aoric atherosclerotic plaques and tended to decrease macrophage plaque infiltration in normoglycemic apolipoprotein E‐deficient mice .…”

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

“…DPP‐4 inhibitors have also been investigated using experimental restenosis models. In wild‐type mice, linagliptin suppresses neointimal hyperplasia after an arterial injury. In addition, the effect of DPP‐4is was examined in Otsuka Long‐Evans Tokushima fatty rats, which is a model of type 2 diabetes with insulin resistance.…”