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Acyl-coenzyme A:cholesterol-acyltransferase (ACAT) inhibitors modulate monocyte adhesion to aortic endothelial cells
U Saxena1, E Ferguson, R S Newton
1Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Insights
Acyl-coenzyme A:cholesterol-acyltransferase (ACAT) inhibitors reduce monocyte adhesion to endothelial cells, a key factor in atherosclerosis development. This effect is mediated by decreased leukotriene B4 (LTB4) production.
Area of Science:
- Cardiovascular Biology
- Atherosclerosis Pathogenesis
- Endothelial Cell Function
Background:
- Monocyte adhesion to the aortic endothelium is a critical early event in atherosclerosis.
- The specific role of endothelial acyl-coenzyme A:cholesterol-acyltransferase (ACAT) in this process remains unclear.
- Lipopolysaccharide (LPS) is known to increase monocyte adhesion to endothelial cells.
Purpose of the Study:
- To investigate the role of endothelial ACAT in regulating monocyte adhesion to the aortic endothelium.
- To determine if ACAT inhibitors can modulate monocyte-endothelial cell interactions.
Main Methods:
- Utilized specific ACAT inhibitors (CI-976 and PD 132301-2) in porcine aortic endothelial cell cultures.
- Assessed monocyte (U937 cells) adhesion to endothelial cells stimulated with LPS.
- Measured endothelial cell ACAT activity and leukotriene B4 (LTB4) synthesis.
- Investigated the effect of exogenous LTB4 on monocyte adhesion in the presence of ACAT inhibitors.
Main Results:
- ACAT inhibitors CI-976 and PD 132301-2 significantly reduced LPS-induced monocyte adhesion to endothelial cells.
- CI-976 treatment decreased both endothelial cell ACAT activity and LTB4 production.
- The inhibitory effect of CI-976 on monocyte adhesion was reversed by the addition of exogenous LTB4.
Conclusions:
- Endothelial ACAT activity contributes to monocyte adhesion, likely through modulation of LTB4 synthesis.
- ACAT inhibitors demonstrate potential as therapeutic agents to reduce monocyte recruitment in atherosclerosis.
- These findings suggest a novel mechanism underlying the anti-atherosclerotic effects of ACAT inhibitors.
Abstract:
Increased monocyte adhesion to aortic endothelium is observed in the pathogenesis of atherosclerosis. The role of endothelial acyl-coenzyme A:cholesterol-acyltransferase (ACAT) in the regulation of monocyte adhesion is not known. To examine the potential role of this enzyme in monocyte adhesion, a specific ACAT inhibitor, CI-976, was utilized. Although the basal adhesion of U937 monocytic cells to porcine aortic endothelial cells was low, treatment of the endothelial cells with lipopolysaccharide (LPS) markedly increased monocyte adhesion. Monocyte adhesion 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 decreased endothelial cell ACAT activity. Since leukotriene B4 (LTB4) is known to promote leukocyte-endothelial cell adhesion, endothelial cell production of this leukotriene was examined after incubation with CI-976. CI-976 treatment markedly decreased LTB4 synthesis. Exogenous LTB4 addition to CI-976 treated cells reversed the effects of this compound on monocyte adhesion. These data demonstrate that ACAT inhibitors decrease monocyte adhesion to endothelial cells. Similar mechanisms may contribute to antiatherosclerotic effects of ACAT inhibitors in vivo.