AUTHOR=Xia Jinggang , Li Qinxue , Liu Yayun , Ren Quanxin , Gao Jinhuan , Tian Yi , Li Jubo , Zhang Baojie , Sun Haichen , Liu Shuang 

TITLE=A GLP-1 Analog Liraglutide Reduces Intimal Hyperplasia After Coronary Stent Implantation via Regulation of Glycemic Variability and NLRP3 Inflammasome/IL-10 Signaling in Diabetic Swine

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00372

DOI=10.3389/fphar.2020.00372

ISSN=1663-9812

ABSTRACT=<sec><title>Objective</title><p>This study aimed to explore whether treatment with the glucagon-like peptide-1 (GLP-1) analog liraglutide reduces intimal hyperplasia after coronary stent implantation <italic>via</italic> regulation of glycemic variability, the NLRP3 inflammasome, and IL-10 in diabetic swine.</p></sec><sec><title>Methods</title><p>Fifteen 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-<italic>α</italic>, interleukin-6, and interleukin-10 were assayed by ELISA. The intima protein expression levels of NLRP3, interleukin-1<italic>β</italic>, interleukin-18 and interleukin-10 were examined using Western blot analysis. Histology was used to evaluate the healing response. In an <italic>in vitro</italic> 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.</p></sec><sec><title>Results</title><p>The 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-<italic>α</italic>, interleukin-6, NLRP3, interleukin-1<italic>β</italic>, and interleukin-18; and higher expression of interleukin-10 compared with those of the DM group (<italic>p</italic> &lt; 0.05). In the <italic>in vitro</italic> study, similar results were obtained in the HG + liraglutide group, and Exe(9–39) abolished the effect of liraglutide (<italic>p</italic> &lt; 0.05).</p></sec><sec><title>Conclusions</title><p>Liraglutide treatment reduces intimal hyperplasia after stent implantation <italic>via</italic> 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.</p></sec>