Linagliptin protects rat carotid artery from balloon injury and activates the NRF2 antioxidant pathway

Abstract

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.

Renoprotective Effects of DPP-4 Inhibitors

“…Nrf2 is known to stimulate the heme oxygenase-1 (HO-1) axis, which is a potent anti-inflammatory target [ 44 ]. It has been reported that DPP-4 inhibitors activate the Nrf2/HO-1 pathway [ 45 , 46 , 47 ]. In addition, Nrf2/Kelch-like ECH-associated protein1 (Keap1) signaling pathways play an important role in preventing oxidative stress [ 48 ].…”

“…BNP is clinically used for the diagnosis and evaluation of CVD [ 69 ]. BNP is synthesized as a 134-amino acid precursor (prepro BNP) that is processed to proBNP [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , …”

Therapeutic Potential of Heme Oxygenase-1 in Aneurysmal Diseases

“…In a rat IA model with ligation of carotid and renal arteries, EPO increased circulating EPCs, reduced the formation and progression of IAs, and reduced the expression of inducible nitric oxide synthase (iNOS) and MMPs [ 85 ]. Dipeptidyl peptidase-4 (DPP-4) inhibitors including sitagliptin have been shown to have beneficial effects in alleviating vascular remodeling and cardiac infarction by reducing ROS via the Nrf2/HO-1 pathway [ 86 , 87 ]. Consistent with this notion, the DPP-4 inhibitor anagliptin inhibited the accumulation of macrophages in IAs and prevented IA growth.…”

IL‐33 promotes the progression of vascular restenosis after carotid artery balloon injury by promoting carotid artery intimal hyperplasia and inflammatory response

“…Carotid artery balloon injury model was constructed as previous reported. 21 Briefly, the male Wistar rats were anaesthetized (3 vol %) with isoflurane by inhalation. Then, the common carotid artery of left side was exposed.…”