GLUCOSE-INDUCED TRANSMIGRATION OF MONOCYTES IS LINKED TO PHOSPHORYLATION OF PECAM-1 IN CULTURED ENDOTHELIAL-CELLS

The adherence of circulating monocytes to the endothelium, their migra tion into the subendothelium, and the subsequent formation of foam cel ls are initial events in the pathogenesis of atherosclerosis. However, the effect of hyperglycemia on the transendothelial migration of mono cytes is not known. Exposure of human umbilical vein endothelial cells (HUVEC) cultured in a Transwell chamber to 25 mM D-glucose (a concent ration representing a hyperglycemic state) for 2 h resulted in a twofo ld increase in the migration of vitamin D-3-differentiated monocyte-li ke HL-60 cells. The migration was inhibited by addition of either an a ntibody to platelet-endothelial cell adhesion molecule-1 (PECAM-1) or a protein kinase C inhibitor, GF-109203X. In HUVEC, high concentration s of D-glucose (25 mM), but not of other sugars such as L-glucose, 2-d eoxyglucose, D-galactose, or D-mannitol, caused a sevenfold increase i n the phosphorylation of PECAM-1 as a result of activation of protein kinase C. The 25 mM D-glucose-induced PECAM-1 phosphorylation and tran smigration of monocyte-like HL-60 cells were further increased by trea tment of HUVEC with the phosphatase inhibitor calyculin A. These resul ts suggest that direct phosphorylation of PECAM-1 in response to eleva ted glucose promotes transendothelial migration of monocytes, contribu ting to accelerated atherogenesis in diabetics.