ACYL-COENZYME A-CHOLESTEROL-ACYLTRANSFERASE (ACAT) INHIBITORS MODULATE MONOCYTE ADHESION TO AORTIC ENDOTHELIAL-CELLS

Increased monocyte adhesion to aortic endothelium is observed in the p athogenesis of atherosclerosis. The role of endothelial acyl-coenzyme A:cholesterol-acyltransferase (ACAT) in the regulation of monocyte adh esion is not known. To examine the potential role of this enzyme in mo nocyte adhesion, a specific ACAT inhibitor, CI-976, was utilized. Alth ough the basal adhesion of U937 monocytic cells to porcine aortic endo thelial cells was low, treatment of the endothelial cells with lipopol ysaccharide (LPS) markedly increased monocyte adhesion. Monocyte adhes ion to LPS-treated endothelial cells was markedly inhibited by CI-976 treatment of the endothelial cells. Similarly, another ACAT inhibitor, PD 132301-2, whose structure is distinct from CI-976, also decreased monocyte adhesion. CI-976 treatment of endothelial cells also decrease d endothelial cell ACAT activity. Since leukotriene B-4 (LTB(4)) is kn own to promote leukocyte-endothelia cell adhesion, endothelial cell pr oduction of this leukotriene was examined after incubation with CI-976 . CI-976 treatment markedly decreased LTB(4) synthesis. Exogenous LTB( 4) addition to CI-976 treated cells reversed the effects of this compo und on monocyte adhesion. These data demonstrate that ACAT inhibitors decrease monocyte adhesion to endothelial cells, Similar mechanisms ma y contribute to antiatherosclerotic effects of ACAT inhibitors in vivo .