Liraglutide, a Glucagon-Like Peptide-1 Receptor Agonist, Attenuates Development of Cardiac Allograft Vasculopathy in a Murine Heart Transplant Model

Background Advances in immunosuppressive therapy have significantly improved short-term but not long-term survival of cardiac transplant recipients; this is largely due to severe cardiac allograft vasculopathy (CAV). Glucagon-like peptide-1 receptor (GLP-1R)-based therapy exerts physiological effects on the cardiovascular system in addition to its traditional role in controlling glucose. We have investigated the effects of liraglutide, a GLP-1R agonist, on the development of CAV in a murine heart transplant model. Methods Heterotopic murine cardiac transplantation was performed with a major histocompatibility complex class II (MHC-II)-mismatched model. Recipient mice were subcutaneously administered vehicle (0.9% saline solution) or liraglutide (300 μg-1kg-112 h-1) from the day of transplantation. Allografts were harvested at 2 or 8 weeks and histologically analyzed. Inflammatory infiltrates were measured by immunohistochemistry, and immunofluorescence and western blotting analyzes were used to evaluate GLP-1R expression and markers of endothelial-to-mesenchymal transition (EndMT) in cardiac allografts and human coronary artery endothelial cells (HCAECs) challenged with transforming growth factor-beta 1 (TGF-β1). Results GLP-1R was predominantly localized to vascular endothelial cells and was up-regulated in cardiac allografts after liraglutide treatment. Liraglutide ameliorated CAV and cardiac fibrosis with reduced inflammatory cell infiltration and down-regulated expression of adhesion molecules. Liraglutide inhibited EndMT in allografts and attenuated EndMT by inhibiting Smad3 activation in TGF-β1-treated HCAECs. Conclusions Administration of liraglutide from the time of transplantation up-regulated GLP-1R in the transplanted heart and reduced cardiac fibrosis, inflammation, and CAV development. Therefore, liraglutide may be a novel therapy for CAV. Corresponding author: Yan-wen Shu, PhD, Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan 430022, China. (shuyanwen@yahoo.com). Corresponding author: Jun Yang, PhD, Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No.1095, Wuhan 430030, Hubei Province, China. (jy@tjh.tjmu.edu.cn). Authorship J.Y, Z.-M.W., and Y.-W.S. conceived and designed the experiments. Z.-M.W., X.-F.H, Y.-K.L., D.-X.M., G.-Y.Z., M.-J.W., and Y.-N.X. performed the experiments. J.Y., Z.-M.W. and X.-F.H. analyzed the data. J.Y. and Z.-M.W. wrote the paper. Disclosure The authors declare no conflicts of interest. Funding The study was supported by the National Nature Science Foundation of China (No. 81373169 to JY). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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