Abstract
BackgroundPrevious animal studies have shown that glucagon-like peptide-1 receptor agonists (GLP-1RAs) suppress arterial restenosis, a major complication of angioplasty, presumably through their direct action on vascular smooth muscle cells. However, the contribution of vascular endothelial cells (VECs) to this process remains unknown. In addition, the potential interference caused by severe hyperglycemia and optimal treatment regimen remain to be determined.MethodsNine-week-old male C57BL6 (wild-type) and diabetic db/db mice were randomly divided into vehicle or liraglutide treatment groups (Day 1), and subject to femoral artery wire injuries (Day 3). The injured arteries were collected on Day 29 for morphometric analysis. Human umbilical vein endothelial cells (HUVECs) were used for in vitro experiments. One-way ANOVA, followed by Tukey’s test, was used for comparisons.ResultsIn wild-type mice, liraglutide treatment (5.7, 17, or 107 nmol/kg/day) dose-dependently reduced the neointimal area (20, 50, and 65%) without inducing systemic effects, and caused an associated decrease in the percentage of vascular proliferating cells. However, these effects were completely abolished by the nitric oxide synthase (NOS) inhibitor N-omega-nitro-l-arginine methyl ester. Next, we investigated the optimal treatment regimen. Early treatment (Days 1–14) was as effective in reducing the neointimal area and vascular cell proliferation as full treatment (Days 1–29), whereas delayed treatment (Days 15–29) was ineffective. In HUVECs, liraglutide treatment dose-dependently stimulated NO production, which was dependent on GLP-1R, cAMP, cAMP-dependent protein kinase, AMP-activated protein kinase (AMPK), and NOS. Subsequently, we investigated the role of liver kinase B (LKB)-1 in this process. Liraglutide increased the phosphorylation of LKB-1, and siRNA-induced LKB-1 knockdown abolished liraglutide-stimulated NO production. In severe hyperglycemic db/db mice, liraglutide treatment also suppressed neointimal hyperplasia, which was accompanied by reductions in vascular cell proliferation and density. Furthermore, liraglutide treatment suppressed hyperglycemia-enhanced vascular inflammation 7 days after arterial injury.ConclusionsWe demonstrate that endothelial cells are targets of liraglutide, and suppress restenosis via endothelial NO. Furthermore, the protective effects are maintained in severe hyperglycemia. Our findings provide an evidence base for a future clinical trial to determine whether treatment with GLP-1RAs represents potentially effective pharmacological therapy following angioplasty in patients with diabetes.
Highlights
Previous animal studies have shown that glucagon-like peptide-1 receptor agonists (GLP-1RAs) suppress arterial restenosis, a major complication of angioplasty, presumably through their direct action on vascular smooth muscle cells
Our findings provide an evidence base for a future clinical trial to determine whether treatment with glucagon like peptide-1 receptor agonist (GLP-1RA) represents potentially effective pharmacological therapy, following percutaneous transluminal angioplasty (PTA) with drugeluting stents (DES) in patients with diabetes
In the present study, we demonstrate for the first time that the anti-restenotic effects of liraglutide are abrogated by the N-omega-nitro-l-arginine methyl ester (l-NAME) nitric oxide synthase (NOS) inhibitor in vivo, and that liver kinase B1 (LKB1) is essential for liraglutide-stimulated endothelial nitric oxide (NO) production in vitro
Summary
Previous animal studies have shown that glucagon-like peptide-1 receptor agonists (GLP-1RAs) suppress arterial restenosis, a major complication of angioplasty, presumably through their direct action on vascular smooth muscle cells. Long-term patency following PTA is markedly improved by the use of drugeluting stents (DES), which strongly suppress neointimal hyperplasia by inhibiting the proliferation of vascular smooth muscle cells (VSMCs) Their beneficial effects are reduced in patients with diabetes [19, 20], leaving them at a high risk for restenosis. The suppression of neointimal hyperplasia by GLP-1RAs was evaluated in vivo using mouse femoral artery wire injury and rat carotid artery balloon injury models [12,13,14,15] These models, unlike atherosclerosis models, facilitate the evaluation of the direct vascular effects of an agent in the absence of metabolic abnormalities such as hypercholesterolemia [21]. The direct vascular effects of GLP-1RAs, identified by these studies, support their potential pharmacological use in the treatment of restenosis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
