Published online before print September 7, 2006, doi: 10.1161/01.RES.0000244088.33375.52
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© 2006 American Heart Association, Inc.
Molecular Medicine |
Sphingosine-1 Phosphate Prevents Monocyte/Endothelial Interactions in Type 1 Diabetic NOD Mice Through Activation of the S1P1 Receptor
From the Robert M. Berne Cardiovascular Research Center (A.M.W., D.T.B., S.S., M.A.M., K.L., C.C.H.); Department of Chemistry (T.L.M.); Department of Biomedical Engineering, Molecular Physiology and Biological Physics (K.L.); and Department of Pharmacology (C.C.H.), University of Virginia, Charlottesville.
Correspondence to Catherine C. Hedrick, PhD, Cardiovascular Research Center, University of Virginia, PO Box 801394, 415 Lane Rd, MR5 Rm G123, Charlottesville, VA 22908. E-mail cch6n{at}virginia.edu
Monocyte recruitment and adhesion to vascular endothelium are key early events in atherosclerosis. We examined the role of sphingosine-1-phosphate (S1P) on modulating monocyte/endothelial interactions in the NOD/LtJ (NOD) mouse model of type 1 diabetes. Aortas from nondiabetic and diabetic NOD mice were incubated in the absence or presence of 100 nmol/L S1P. Fluorescently labeled monocytes were incubated with the aortas. Aortas from NOD diabetic mice bound 7-fold more monocytes than nondiabetic littermates (10±1 monocytes bound/field for nondiabetic mice vs 74±12 monocytes bound/field for diabetic mice, P<0.0001). Incubation of diabetic aortas with 100 nmol/L S1P reduced monocyte adhesion to endothelium by 90%. We found expression of S1P1, S1P2, and S1P3 receptors on NOD aortic endothelial cells. The S1P1 receptor-specific agonist SEW2871 inhibited monocyte adhesion to diabetic aortas. Studies in diabetic S1P3-deficient mice revealed that the S1P3 receptor did not play a pivotal role in this process. S1P reduced endothelial VCAM-1 induction in type 1 diabetic NOD mice, most likely through inhibition of nuclear factor 
B translocation to the nucleus. Thus, S1P activation of the S1P1 receptor functions in an antiinflammatory manner in type 1 diabetic vascular endothelium to prevent monocyte/endothelial interactions. S1P may play an important role in the prevention of vascular complications of type 1 diabetes.
Key Words: endothelial • NF-B • type 1 diabetes • sphingosine-1-phosphate • adhesion molecules
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