Effect of a Dipeptidyl Peptidase-IV Inhibitor, Des-Fluoro-Sitagliptin, on Neointimal Formation after Balloon Injury in Rats

Abstract

BackgroundRecently, it has been suggested that enhancement of incretin effect improves cardiac function. We investigated the effect of a DPP-IV inhibitor, des-fluoro-sitagliptin, in reducing occurrence of restenosis in carotid artery in response to balloon injury and the related mechanisms.Methods and FindingsOtsuka Long-Evans Tokushima Fatty rats were grouped into four: control (normal saline) and sitagliptin 100, 250 and 500 mg/kg per day (n = 10 per group). Sitagliptin or normal saline were given orally from 1 week before to 2 weeks after carotid injury. After 3 weeks of treatment, sitagliptin treatment caused a significant and dose-dependent reduction in intima-media ratio (IMR) in obese diabetic rats. This effect was accompanied by improved glucose homeostasis, decreased circulating levels of high-sensitivity C-reactive protein (hsCRP) and increased adiponectin level. Moreover, decreased IMR was correlated significantly with reduced hsCRP, tumor necrosis factor-α and monocyte chemoattractant protein-1 levels and plasminogen activator inhibitor-1 activity. In vitro evidence with vascular smooth muscle cells (VSMCs) demonstrated that proliferation and migration were decreased significantly after sitagliptin treatment. In addition, sitagliptin increased caspase-3 activity and decreased monocyte adhesion and NFκB activation in VSMCs.ConclusionsSitagliptin has protective properties against restenosis after carotid injury and therapeutic implications for treating macrovascular complications of diabetes.

Dipeptidyl peptidase-4 inhibition by gemigliptin prevents abnormal vascular remodeling via NF-E2-related factor 2 activation

“…This damage occurs via excess ROS production in the vasculature that modulates migration, adhesion, contractility, proliferation and hypertrophy, angiogenesis, apoptosis, and aging [5,35]. The anti-proliferative and anti-migratory effects of gemigliptin in our study are similar to the findings of Lim et al [38]. An understanding of the anti-oxidative mechanism of pharmacological DPP-4 inhibitors may be important to reducing the morbidity and mortality associated with oxidative stress resulting from metabolic disturbances such as diabetes and the ensuing cardiovascular diseases.…”

Vildagliptin Stimulates Endothelial Cell Network Formation and Ischemia-induced Revascularization via an Endothelial Nitric-oxide Synthase-dependent Mechanism

“…Treatment with sitagliptin attenuated intimal hyperplasia in response to vascular injury in rats (9), and both sitagliptin and alogliptin reduced atherosclerotic lesions in a mouse model (10,11). Alogliptin treatment was also found to modulate endotheliumdependent vasodilation in mouse aortic segments (12), and sita-gliptin augments neovascularization by increasing circulating endothelial progenitor cells in vivo (13).…”

The dipeptidyl peptidase-IV inhibitor inhibits the expression of vascular adhesion molecules and inflammatory cytokines in HUVECs via Akt- and AMPK-dependent mechanisms

“…Apo E −/− mice is a representative atherosclerotic animal model by the deletion of Apo E, which plays a requisite role in remnant lipoprotein clearance and the suppression of T-cell mediated cytokine production (Curtiss, 2000). In addition, sitagliptin reduced restenosis in obese type 2 diabetic rats following balloon injury to the carotid artery by suppressing the proliferation of vascular smooth muscle cells, promoting apoptosis and reducing inflammatory process (Lim et al, 2012). However, these cardiobeneficial effects of DPP-IV inhibitor have mostly been attributed to indirect effects through increased GLP-1 bioavailability in animal models.…”