Involvement of fibrinolytic regulators in adhesion of monocytes to vascular endothelial cells induced by glycated LDL and to aorta from diabetic mice

• Published in: Journal of leukocyte biology Vol. 95; no. 6; pp. 941 - 949
• Main Authors: Zhao, Ruozhi, Ren, Song, Moghadasain, Mohammed H., Rempel, Julia D., Shen, Garry X.
• Format: Journal Article
• Language: English
• Published: United States 01-06-2014
• Subjects: Animals; Aorta - cytology; Cell Adhesion; Cells, Cultured; Diabetes Mellitus, Type 2 - complications; DNA-Binding Proteins - physiology; Endothelial Cells - cytology; Heat Shock Transcription Factors; Humans; Intercellular Adhesion Molecule-1 - analysis; leptin‐receptor knockout; Lipoproteins, LDL - physiology; Male; Mice; Mice, Inbred C57BL; Monocytes - physiology; NADPH Oxidases - physiology; P-Selectin - analysis; PAI‐1; Plasminogen Activator Inhibitor 1 - analysis; Plasminogen Activator Inhibitor 1 - physiology; Transcription Factors - physiology; uPA; Urokinase-Type Plasminogen Activator - physiology; vascular inflammation; PAI-1; leptin-receptor knockout; vascular inflammation; uPA
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.0513262

Oxidative stress and fibrinolytic regulators are involved in glycated LDL‐induced monocyte adhesion to vascular endothelial cells and increased monocyte adhesion in diabetic mice.
Diabetes mellitus accelerates the development of atherosclerotic cardiovascular diseases. Monocyte adhesion is an early cellular event of atherogenesis. Elevated levels of glyLDL were common in diabetic patients. Our previous studies indicated that HSF1 and p22‐phox (a subunit of the NOX complex) were involved in glyLDL‐induced up‐regulation of PAI‐1 in vascular EC. The present study demonstrated that glyLDL significantly increased the adhesion of monocytes to the surface of cultured human umbilical vein or PAEC. Transfection of siRNA for PAI‐1, p22‐phox, or HSF1 in EC prevented glyLDL‐induced monocyte adhesion to EC. uPA siRNA increased monocyte adhesion to EC. Exogenous uPA reduced monocyte adhesion induced by glyLDL or uPA siRNA. Exogenous PAI‐1 restored monocyte adhesion to EC inhibited by PAI‐1 siRNA or uPA. GlyLDL‐induced monocyte adhesion to EC was inhibited by treatment of EC with RAP, an antagonist for LRP, and enhanced by uPAR antibody. The adhesion of monocytes to aorta from leptin db/db diabetic mice was significantly greater than to that from control mice, which was associated with elevated contents of PAI‐1, uPA, p22‐phox, and HSF1 in hearts of db/db mice. The results suggest that oxidative stress and fibrinolytic regulators (PAI‐1, uPA, and uPAR) are implicated in the modulation of glyLDL‐induced monocyte adhesion to vascular endothelium, which may play a crucial role in vascular inflammation under diabetes‐associated metabolic disorder.