Published online before print September 7, 2006, doi: 10.1161/01.RES.0000244088.33375.52
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Submitted on February 24, 2006
Revised on August 17, 2006
Accepted on August 24, 2006
Sphingosine-1 Phosphate Prevents Monocyte/Endothelial Interactions in Type 1 Diabetic NOD Mice Through Activation of the S1P1 Receptor
Angela M. Whetzel ;
From the Robert M. Berne Cardiovascular Research Center (A.M.W., D.T.B., S.S., T.L.M., 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.
* To whom correspondence should be addressed. 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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