Diabetic conditions promote binding of monocytes to vascular smooth muscle cells and their subsequent differentiation.
Diabetes is associated with significantly accelerated rates of atherosclerosis, key features of which include the presence of excessive macrophage-derived foam cells in the subendothelial space. We examined the hypothesis that enhanced monocyte-vascular smooth muscle cell (VSMC) interactions leading to subendothelial monocyte retention and differentiation to macrophages under diabetic conditions may be underlying mechanisms. Human aortic VSMCs (HVSMCs) treated with diabetic stimuli high glucose (HG) or S100B, a ligand of the receptor for advanced glycation end products, exhibited significantly increased binding of THP-1 monocytic cells. Diabetic stimuli increased the expression of the adhesive chemokine fractalkine (FKN) in HVSMCs. Pretreatment of HVSMCs with FKN or monocyte chemoattractant protein-1 (MCP-1) neutralizing antibodies significantly inhibited monocyte-VSMC binding, whereas monocytes treated with FKN showed enhanced binding to VSMC. Mouse aortic VSMCs (MVSMCs) derived from type 2 diabetic db/db mice exhibited significantly increased FKN levels and binding to mouse WEHI78/24 monocytic cells relative to nondiabetic control db/+ cells. The enhanced monocyte binding in db/db cells was abolished by both FKN and MCP-1 antibodies. Endothelium-denuded aortas from db/db mice and streptozotocin-induced diabetic mice also exhibited enhanced FKN expression and monocyte binding, relative to respective controls. Coculture with HVSMCs increased CD36 expression in THP-1 cells, and this was significantly augmented by treatment of HVSMCs with S100B or HG. CD36 mRNA and protein levels were also significantly increased in WEHI78/24 cells after coincubation with db/db MVSMCs relative to control MVSMCs. These results demonstrate that diabetic conditions may accelerate atherosclerosis by inducing key chemokines in the vasculature that promote VSMC-monocyte interactions, subendothelial monocyte retention, and differentiation.
Meng
Li
L
Department of Diabetes, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Park
Jehyun
J
Cai
Qiangjun
Q
Lanting
Linda
L
Reddy
Marpadga A
MA
Natarajan
Rama
R
D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D002448:Cell Adhesion; D002450:Cell Communication; D002454:Cell Differentiation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism / Q000494:pharmacology; D054428:Chemokine CX3CL1 / Q000378:metabolism / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009000:Monocytes / Q000378:metabolism / Q000473:pathology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009414:Nerve Growth Factors / Q000494:pharmacology; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000494:pharmacology; D013311:Streptozocin
D018955:CD36 Antigens; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; C579159:S100b protein, mouse; D013311:Streptozocin; D005947:Glucose