We have previously shown that
glucosamine promotes endoplasmic reticulum (ER) stress in vascular cells leading to both
inflammation and
lipid accumulation--the hallmark features of
atherosclerosis. Pretreatment with
glycogen synthase kinase (GSK)-3 inhibitors protects cultured cells from ER stress-induced dysfunction. Here we evaluate the potential role of
GSK-3 on the pro-atherogenic effects of
hyperglycemia and ER stress. We show that GSK-3-deficient mouse embryonic fibroblasts do not accumulate unesterified
cholesterol under conditions of ER stress. Furthermore,
GSK-3 inhibitors, including
valproate, attenuate ER stress-induced unesterified
cholesterol accumulation in wild-type mouse embryonic fibroblasts. In vivo we show that hyperglycemic
apoE-deficient mice have accelerated
atherogenesis at the aortic root compared with normoglycemic control mice. Mice fed a diet supplemented with 625 mg/kg
valproate have significantly reduced lesion volume relative to nonsupplemented controls.
Valproate supplementation has no apparent effect on the plasma levels of either
glucose or
lipids or on the expression of diagnostic markers of ER stress in the lesion. Significant reductions were observed in total hepatic
lipids (>50.4%) and hepatic
GSK-3beta activity (>55.8%) in mice fed the
valproate diet. In conclusion, dietary supplementation with low levels of
valproate significantly attenuates
atherogenesis in hyperglycemic
apoE-deficient mice. The in vivo anti-atherogenic effects of
valproate are consistent with its ability to inhibit
GSK-3 and interfere with pro-atherogenic ER stress signaling pathways in vitro.