Endothelial cell dysfunction may play an important role in the development of various vascular diseases, including atherosclerosis. Here we investigated whether lithium chloride (LiCl), an inhibitor of glycogen synthase kinase-3β (GSK-3β), could counteract atherosclerosis induced by a high-fat diet in ApoE⁻/⁻ mice. Ten-week-old male mice were randomly divided into four groups: normal chow diet, high-fat diet (i.e., 20% fat and 0.5% cholesterol), high-fat diet with LiCl treatment for 6 weeks and high-fat diet with LiCl treatment for 14 weeks. Examination of plasma profiles indicated that blood glucose levels were significantly decreased by LiCl treatment. Supplementation with LiCl dramatically reduced atherosclerotic lesion formation in the aorta and aortic root. LiCl treatment also decreased vascular cell adhesion molecule (VCAM)-1 expression and macrophage infiltration into atherosclerotic lesion areas within the aortic valve. In addition, inhibition of GSK-3β by TDZD-8, SB216763, and LiCl, as well as adenoviral transduction with a catalytically inactive GSK-3β, reduced palmitate-induced VCAM-1 expression through inhibition of JNK activity and degradation of Iκ-Bα in human umbilical vein endothelial cells (HUVECs). The results of the present study suggest that LiCl alleviates palmitate-induced cell adhesion molecule expression in HUVECs and decreases atherosclerosis induced by a high-fat diet in ApoE⁻/⁻ mice. Thus, GSK-3β may be involved in the development of atherosclerosis induced by a high-fat diet in ApoE⁻/⁻ mice.
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