Yingxian Zhang1, Yu Zheng2, Jin Li3, Ling Nie4, Yijie Hu5, Fangjie Wang3, Hongmei Liu3, Steve M Fernandes6, Qianjin Zhong5, Xiaohui Li7, Ronald L Schnaar8, Yi Jia9. 1. Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, ChongQing 400038, China; Department of Pharmacy, The Third Affiliated Hospital, ChongQing Medical University, Yubei, Chongqing 401120, China. 2. Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, ChongQing 400038, China; Department of Pharmacy, Hainan Western Central Hospital, Danzhou, Hainan 571799, China. 3. Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, ChongQing 400038, China. 4. Department of Nephrology, Xinqiao Hospital, Third Military Medical University, ChongQing 400037, China. 5. Department of Cardiovascular Surgery, Research Institute of Surgery, Daping Hospital, Third Military Medical University, ChongQing 400042, China. 6. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 7. Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, ChongQing 400038, China. Electronic address: xhl@tmmu.edu.cn. 8. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: schnaar@jhu.edu. 9. Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, ChongQing 400038, China. Electronic address: jy@tmmu.edu.cn.
Abstract
AIM: Inflammation is a driving force in development of atherosclerosis, and hyperglycemia is a significant risk factor for angiopathy. Siglec-9, expressed on human neutrophils and macrophages, engages specific glycan ligands on tissues to diminish ongoing inflammation. MATERIALS AND METHOD: Siglec-9 ligands on human aorta were characterized and the effects of high glucose exposure on the expression of ligands for Siglec-9 on human umbilical vein endothelial cells (HUV-EC-C) in vitro and ligands for the comparable siglec (Siglec-E) on mouse aorta in vivo were studied. KEY FINDINGS: Siglec-9 ligands were expressed broadly on human aorta, as well as on HUV-EC-C. Siglec-9 ligands on HUV-EC-C were sharply up-regulated under high glucose exposure in vitro, as were Siglec-E ligands on the aortas of hyperglycemic mice. Exposure of HUV-EC-C to high-glucose resulted in consistent inhibitory changes in co-cultured macrophages including increased apoptosis and decreased phagocytosis. Control of Siglec-9 ligand expression on HUV-EC-C was downstream of changes in an enzyme involved in their biosynthesis, UDP-galactose-4-epimerase (GALE) and increased cellular N-acetylgalactosamine. The alteration of GALE was associated with the regulatory microRNA hsa-let-7f. SIGNIFICANCE: We conclude that exposure to high-glucose results in up-regulation of immune inhibitory Siglec-9 sialoglycan ligands on aorta and HUV-EC-C cells downstream of altered GALE and GalNAc expression, resulting in up-regulation of apoptosis and decrease of phagocytic activity of macrophages. Changes in Siglec-9 sialoglycan ligand expression on vascular endothelial cells may be a natural response to the initial steps of atherosclerosis and might be a potential target to regulate inflammation in diabetic angiopathy.
AIM: Inflammation is a driving force in development of atherosclerosis, and hyperglycemia is a significant risk factor for angiopathy. Siglec-9, expressed on human neutrophils and macrophages, engages specific glycan ligands on tissues to diminish ongoing inflammation. MATERIALS AND METHOD:Siglec-9 ligands on human aorta were characterized and the effects of high glucose exposure on the expression of ligands for Siglec-9 on human umbilical vein endothelial cells (HUV-EC-C) in vitro and ligands for the comparable siglec (Siglec-E) on mouse aorta in vivo were studied. KEY FINDINGS:Siglec-9 ligands were expressed broadly on human aorta, as well as on HUV-EC-C. Siglec-9 ligands on HUV-EC-C were sharply up-regulated under high glucose exposure in vitro, as were Siglec-E ligands on the aortas of hyperglycemic mice. Exposure of HUV-EC-C to high-glucose resulted in consistent inhibitory changes in co-cultured macrophages including increased apoptosis and decreased phagocytosis. Control of Siglec-9 ligand expression on HUV-EC-C was downstream of changes in an enzyme involved in their biosynthesis, UDP-galactose-4-epimerase (GALE) and increased cellular N-acetylgalactosamine. The alteration of GALE was associated with the regulatory microRNA hsa-let-7f. SIGNIFICANCE: We conclude that exposure to high-glucose results in up-regulation of immune inhibitory Siglec-9 sialoglycan ligands on aorta and HUV-EC-C cells downstream of altered GALE and GalNAc expression, resulting in up-regulation of apoptosis and decrease of phagocytic activity of macrophages. Changes in Siglec-9 sialoglycan ligand expression on vascular endothelial cells may be a natural response to the initial steps of atherosclerosis and might be a potential target to regulate inflammation in diabetic angiopathy.