Involvement of fibrinolytic regulators in adhesion of monocytes to vascular endothelial cells induced by glycated LDL and to aorta from 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.
Departments of Internal Medicine and.
Ruozhi
R
Zhao
Departments of Internal Medicine and.
Song
S
Ren
Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Mohammed H
MH
Moghadasain
Departments of Internal Medicine and.
Julia D
JD
Rempel
Departments of Internal Medicine and garry.shen@med.umanitoba.ca.
Garry X
GX
Shen
D000818:Animals; D001011:Aorta / Q000166:cytology*; D002448:Cell Adhesion; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D042783:Endothelial Cells / Q000166:cytology*; D017127:Glycation End Products, Advanced; D000076249:Heat Shock Transcription Factors; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008077:Lipoproteins, LDL / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology*; D019255:NADPH Oxidases / Q000502:physiology; D019007:P-Selectin / Q000032:analysis; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*; D000093844:Glycated Proteins
D004268:DNA-Binding Proteins; D017127:Glycation End Products, Advanced; D000076249:Heat Shock Transcription Factors; D018799:Intercellular Adhesion Molecule-1; D008077:Lipoproteins, LDL; D019255:NADPH Oxidases; D019007:P-Selectin; D017395:Plasminogen Activator Inhibitor 1; D014157:Transcription Factors; D014568:Urokinase-Type Plasminogen Activator; C490017:Hsf1 protein, mouse; C031797:glycated lipoproteins, LDL; D000093844:Glycated Proteins; C515768:Cyba protein, rat
PAI-1; leptin-receptor knockout; uPA; vascular inflammation