linagliptin and Neointima

Percutaneous coronary intervention (PCI) is main treatment for acute coronary syndrome (ACS). However, restenosis caused by PCI-induced injury influences the outcome of patients. Linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has been reported to ameliorate intimal hyperplasia post vascular injury. The underlying mechanisms by which linagliptin protects against balloon injury are unclear and require to be explored. Herein, Wistar rats with carotid artery balloon injury were given 1, 2 or 3 mg/kg/day linagliprin for 6 weeks. We found that linagliptin attenuated vascular injury-mediated neointima formation in rats without affecting body weight and blood glucose levels. ELISA results indicated that linagliptin significantly reduced overproduction of cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 post balloon injury. By detecting the level of malondialdehyde (MDA) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), we found that linagliptin prevented balloon injury-induced oxidative stress. Additionally, linagliptin decreased the level of Kelch ECH-associating protein 1 (KEAP1) compared with injury group. Results of Western blots and electrophoretic mobility shift assay (EMSA) demonstrated that linagliptin augmented nuclear accumulation of nuclear factor-E2-related factor 2 (NRF2) and its binding ability to target genes in rats with balloon injury. Moreover, heme oxygenase-1 (HO-1) and NAD (P) H quinine oxidoreductase 1 (NQO1), two downstream targets of NRF2, were further up-regulated after linagliptin treatment compared with injury group. In conclusion, our data suggest that linagliptin protects carotid artery from balloon injury-induced neointima formation and activates the NRF2 antioxidant pathway.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Animals; Carotid Arteries; Carotid Artery Injuries; Coronary Restenosis; Cytokines; Dipeptidyl-Peptidase IV Inhibitors; Glutathione Peroxidase; Inflammation Mediators; Linagliptin; Male; Malondialdehyde; Neointima; NF-E2-Related Factor 2; Oxidative Stress; Rats, Wistar; Superoxide Dismutase; Up-Regulation

Neointima hyperplasia is the pathological basis of atherosclerosis and restenosis which have been associated with diabetes mellitus (DM). It is controversial for linagliptin and metformin to protect against vascular neointimal hyperplasia caused by DM. Given the combined therapy of linagliptin and metformin in clinical practice, we investigated whether the combination therapy inhibited neointimal hyperplasia in the carotid artery in diabetic rats.. We demonstrated that the potential protection of the combined use of linagliptin and metformin on VSMC remodeling through AMPK/Nox4 signal pathway, resulting in the improvement of neointima hyperplasia in diabetic rats. This study provided new therapeutic strategies for vascular stenosis associated with diabetes.

Topics: AMP-Activated Protein Kinases; Animals; Aorta, Thoracic; Carotid Arteries; Constriction, Pathologic; Diabetes Mellitus, Experimental; Endothelium, Vascular; Flow Cytometry; Hyperplasia; Linagliptin; Male; Metformin; Muscle, Smooth, Vascular; NADPH Oxidase 4; NADPH Oxidases; Neointima; Oxygen; Rats; Rats, Sprague-Dawley; RNA Interference; Signal Transduction; Vascular Remodeling; Vasoconstriction; Wound Healing

Recently, 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).. Six-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.. Linagliptin 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.. Linagliptin attenuates neointima formation after vascular injury and VSMC proliferation beyond the glucose-lowering effect.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Hypoglycemic Agents; Linagliptin; Male; Mice, Inbred C57BL; Neointima; Purines; Quinazolines; Vascular System Injuries