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A subset of mice from each group was supplemented with sodium valproate (625 mg\/kg), a compound with GSK3 inhibitory activity. At 15 and 24 weeks of age, markers of ER stress, lipid accumulation, GSK3\u03b2 phosphorylation, and GSK3\u03b2 activity were analyzed in liver and aorta. Atherosclerotic lesions were examined and quantified. Hyperglycemia, hyperhomocysteinemia, and high-fat diet significantly enhanced GSK3\u03b2 activity and also increased hepatic steatosis and atherosclerotic lesion volume compared with controls. Valproate supplementation blocked GSK3\u03b2 activation and attenuated the development of atherosclerosis and the accumulation of hepatic lipids in each of the models examined. The mechanism by which GSK3\u03b2 activity is regulated in these models likely involves alterations in phosphorylation at serine 9 and tyrosine 216.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion\u2014<\/jats:title><jats:p>These findings support the existence of a common mechanism of accelerated atherosclerosis involving ER stress signaling through activation of GSK3\u03b2. Furthermore, our results suggest that atherosclerosis can be attenuated by modulating GSK3\u03b2 phosphorylation.<\/jats:p><\/jats:sec>","DOI":"10.1161\/atvbaha.111.237941","type":"journal-article","created":{"date-parts":[[2011,10,14]],"date-time":"2011-10-14T04:35:27Z","timestamp":1318566927000},"page":"82-91","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":49,"title":["Endoplasmic Reticulum Stress and Glycogen Synthase Kinase-3\u03b2 Activation in Apolipoprotein E\u2013Deficient Mouse Models of Accelerated Atherosclerosis"],"prefix":"10.1161","volume":"32","author":[{"given":"Cameron S.","family":"McAlpine","sequence":"first","affiliation":[{"name":"From the Departments of Medicine (C.S.M., G.H.W.) and Biochemistry and Biomedical Sciences (A.J.B., G.H.W.) and the Thrombosis and Atherosclerosis Research Institute (C.S.M., A.J.B., M.I.K., Y.S., G.H.W.), McMaster University, Hamilton, Ontario, 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