Backgrounds: The uptake of oxidized low‐density lipoprotein (oxLDL) in macrophages in atherosclerotic lesions progresses atherosclerosis. Acamprosate (ACAM), one of the drugs used in the treatment of alcohol-dependence, is a N-methyl-D-aspartic acid receptor (NMDAR) antagonist. Additionally, blockade of peripheral NMDAR attenuates the LPS-induced lung injury in animal model. In the present study, we investigated effects of ACAM on atherosclerotic plaque formation in apolipoprotein E knockout (ApoE KO) mice and on oxLDL uptake in macrophages.
Methods and results: ApoE KO mice (8-week-old) were fed a high-fat diet and intraperitoneally injected with vehicle (saline) or ACAM (200 mg kg^-1 day^-1) for 21 days. Atherosclerotic lesions were histologically analyzed. ACAM significantly inhibited atherosclerotic plaque formation in the aortic arch and aortic root of ApoE KO mice. Additionally, by immunohistochemistry, ACAM reduced the area of monocyte/macrophage in atherosclerotic plaques.
Next, to assess the effects of ACAM on oxLDL uptake in macrophage, macrophages were treated with 300 μM ACAM for 24h and then DiI-labeled oxLDL (DiI-oxLDL) was added to the celles for 4 h. ACAM significantly decreased DiI-oxLDL uptake in cells. In addition, ACAM (0-300 μM) dose-dependently decreased the protein expression of LOX-1 and CD36 scavenger receptors in cells, by western blot analyses.
Conclusion: ACAM attenuates oxLDL accumulation in macrophages by decreasing the expression of LOX-1 and CD36 and thereby ACAM may inhibit the atherosclerotic plaque formation.