Abstract
ObjectiveThis study aimed to explore whether treatment with the glucagon-like peptide-1 (GLP-1) analog liraglutide reduces intimal hyperplasia after coronary stent implantation via regulation of glycemic variability, the NLRP3 inflammasome, and IL-10 in diabetic swine.MethodsFifteen pigs were divided into a diabetes mellitus (DM) group (n = 6), a DM + liraglutide treatment group (L group) (n = 6) and a sham group (n = 3). A total of 24 everolimus-eluting stents were implanted in the left anterior descending and right coronary arteries at 3 weeks. A novel continuous glucose monitoring system (GMS) was used for 2 weeks. The means and standard deviations (SDs) were measured and calculated by the GMS. At 22 weeks, the lumen area (LA), neointimal thickness (NIT), neointimal area (NIA), and percent area stenosis (%AS) were analyzed by optical coherence tomography. Plasma tumor necrosis factor-α, interleukin-6, and interleukin-10 were assayed by ELISA. The intima protein expression levels of NLRP3, interleukin-1β, interleukin-18 and interleukin-10 were examined using Western blot analysis. Histology was used to evaluate the healing response. In an in vitro study, THP-1 cells were divided into control, high glucose (HG), HG + liraglutide, and HG + liraglutide + Exe(9–39) (a GLP-1 receptor inhibitor) groups.ResultsThe L group had a lower SD, NIT, NIA, and %AS; a larger LA; reduced inflammation and injury scores; lower expression levels of tumor necrosis factor-α, interleukin-6, NLRP3, interleukin-1β, and interleukin-18; and higher expression of interleukin-10 compared with those of the DM group (p < 0.05). In the in vitro study, similar results were obtained in the HG + liraglutide group, and Exe(9–39) abolished the effect of liraglutide (p < 0.05).ConclusionsLiraglutide treatment reduces intimal hyperplasia after stent implantation via regulation of glycemic variability, the NLRP3 inflammasome, and IL-10 in diabetic pigs in a GLP-1 receptor-dependent manner. Reducing the inflammation induced by glycemic variability may be one of the cardioprotective mechanisms of liraglutide.
Highlights
Diabetes mellitus (DM) is continuously increasing globally and is associated with a wide spectrum of vascular complications, coronary artery disease (CAD)
Fasting blood glucose (FBG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and TG were similar between the DM and L groups (p > 0.05)
We found that (1) liraglutide treatment was associated with increased lumen area (LA) and reduced neointimal thickness (NIT), neointimal area (NIA), and %AS compared with those of the DM group; (2) liraglutide treatment was associated with reduced glycemic variability (SD); (3) liraglutide treatment was associated with reduced inflammation and injury scores in semiquantitative stented vascular histological analysis, reduced expression levels of NOD-like receptor family pyrin domain containing 3 (NLRP3), IL-1b, IL-18, tumor necrosis factor-alpha (TNF-a), IL-6 and increased expression of IL-10; and (4) the beneficial effect of liraglutide in regulating the NLRP3 inflammasome and IL-10 was dependent on the glucagon-like peptide-1 (GLP-1) receptor
Summary
Diabetes mellitus (DM) is continuously increasing globally and is associated with a wide spectrum of vascular complications, coronary artery disease (CAD). In the LEADER trial, liraglutide treatment significantly reduced major cardiac events in diabetic patients who had a high risk of cardiovascular disease (Kim and Kim, 2017), which may be explained by the antiatherosclerotic and anti-inflammatory mechanisms of liraglutide (Hirano and Mori, 2016). The effects and possible mechanism of liraglutide on neointimal hyperplasia after coronary stent implantation remain elusive. Accumulating evidence suggests roles for NOD-like receptor family pyrin domain containing 3 (NLRP3) in mediating inflammation and interleukin-10 (IL-10) in mediating anti-inflammatory effects in diabetes and cardiovascular diseases (Groslambert and Py, 2018). The present study aimed to determine whether the glucagon-like peptide-1 (GLP-1) analog liraglutide reduces intimal hyperplasia after coronary stent implantation and inflammatory regulation in diabetic pigs
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