Reduced monocyte adhesion to aortae of diabetic plasminogen activator inhibitor-1 knockout mice

• Published in: Inflammation research Vol. 66; no. 9; pp. 783 - 792
• Main Authors: Zhao, Ruozhi, Le, Khuong, Moghadasian, Mohammed H., Shen, Garry X.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.09.2017; Springer Nature B.V
• Subjects: Adhesion; Allergology; Animals; Antigens - blood; Aorta; Aorta - physiology; Biomedical and Life Sciences; Biomedicine; Cell Adhesion; Chemokine CCL2 - blood; Chemokine CCL2 - immunology; Dermatology; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - immunology; Diabetes Mellitus, Experimental - physiopathology; Endothelial cells; Enzyme-linked immunosorbent assay; Fibrin; Human Umbilical Vein Endothelial Cells - immunology; Human Umbilical Vein Endothelial Cells - physiology; Humans; Immune system; Immunology; Inflammation; Inhibitors; Lipoproteins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocyte chemoattractant protein 1; Monocytes; Monocytes - immunology; Monocytes - physiology; Neurology; Original Research Paper; Pharmacology/Toxicology; Plasminogen activator inhibitors; Polyamide-imides; Proteins; Receptors, Urokinase Plasminogen Activator - immunology; Regulators; Rheumatology; Ribonucleic acid; RNA; RNA, Small Interfering - genetics; RNA-mediated interference; Rodents; Serpin E2 - genetics; Serpin E2 - immunology; siRNA; Streptozocin; TLR4 protein; Toll-Like Receptor 4 - genetics; Toll-like receptors; Transfection; Tumor necrosis factor; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology; Tumor necrosis factor-TNF; U-Plasminogen activator; Umbilical vein; Urokinase; Urokinase-Type Plasminogen Activator - immunology; Western blotting; Plasminogen activator inhibitor-1 knockout mice; Monocyte adhesion; Toll-like receptor-4; Tumor necrosis factor-α; Streptozotocin-induced diabetes
• ISSN: 1023-3830; 1420-908X; 1420-908X
• DOI: 10.1007/s00011-017-1057-z

Objective and design To determine the requirement of plasminogen activator inhibitor-1-knockout (PAI-1) for monocyte adhesion in animals and cells under diabetic conditions. Methods and subjects Monocyte adhesion assay, enzyme-linked immunosorbent assay, and Western blotting were used in analyzing samples from PAI-1-knockout (PAI-1-KO) mice or cultured human umbilical vein endothelial cells (HUVEC). Treatments Diabetes in PAI-1-KO and wild-type mice was induced by intraperitoneal injection of streptozotocin (STZ). HUVEC was transfected with short interference RNA (siRNA) against PAI-1, tumor necrosis factor-α (TNFα), or toll-like receptor (TLR4), and then was treated with glycated low-density lipoproteins (glyLDL). Results The adhesion of monocytes to aortic intima was reduced in PAI-1-KO mice, which was associated with decreased levels of TNFα and monocyte chemotactic protein-1 (MCP-1) in plasma and cardiovascular tissue, and increased abundances of urokinase plasminogen activator (uPA) and uPA receptor (uPAR) in cardiovascular tissue compared to wild-type mice. Significant reductions in monocyte adhesion, inflammatory, and fibrinolytic regulators were detected in cardiovascular tissue or plasma in diabetic PAI-1-KO mice compared to wild-type diabetic mice. Transfection of PAI-1, TNFα or TLR4 siRNA to HUVEC inhibited glyLDL-induced monocyte adhesion to EC. PAI-1 siRNA inhibited the abundances of TLR4 and TNFα in EC. Conclusion The findings suggest that PAI-1 is required for diabetes-induced monocyte adhesion via interactions with uPA/uPAR, and it also regulates TLR4 and TNFα expression in vascular EC. Inhibition of PAI-1 potentially reduces vascular inflammation under diabetic condition.