title: Deletion of Myeloid GSK3α Attenuates Atherosclerosis and Promotes an M2 Macrophage Phenotype.
abstract: OBJECTIVE
  Glycogen synthase kinase (GSK)-3α/β has been implicated in the pathogenesis of diabetes mellitus, cancer, Alzheimer, and atherosclerosis. The tissue- and homolog-specific functions of GSK3α and β in atherosclerosis are unknown. This study examines the effect of hepatocyte or myeloid cell deletion of GSK3α or GSK3β on atherosclerosis in low-density lipoprotein receptor (LDLR)(-/-) mice.
  
  
  RESULTS
  We ablated GSK3α or GSK3β expression in hepatic or myeloid cells of LDLR(-/-) mice, and mice were fed a high-fat diet for 10 weeks. GSK3α or GSK3β deficiency in hepatic or myeloid cells did not affect metabolic parameters, including plasma lipid levels. Hepatic deletion of GSK3α or GSK3β did not affect the development of atherosclerosis or hepatic lipid content. Myeloid deletion of GSK3α, but not of GSK3β, reduced atherosclerotic lesion volume and lesion complexity. Mice lacking GSK3α in myeloid cells had a less inflammatory and more anti-inflammatory plasma cytokine profile. Macrophages within atherosclerotic lesions of myeloid GSK3α-deficient mice, but not of GSK3β-deficient mice, displayed reduced expression of markers associated with M1 macrophage polarization and enhanced expression of the M2 markers. Finally, bone marrow-derived macrophages were isolated and differentiated into classical M1 macrophages or alternative M2 macrophages in vitro. GSK3α deletion, but not GSK3β deletion, attenuated the expression of genes associated with M1 polarization while promoting the expression of genes associated with M2 polarization by modulating STAT3 and STAT6 activation.
  
  
  CONCLUSIONS
  Our findings suggest that deletion of myeloid GSK3α attenuates the progression of atherosclerosis by promoting an M2 macrophage phenotype.
authors.affiliation: From the Departments of Medicine (C.S.M., Y.S., G.H.W.), Biochemistry and Biomedical Sciences (N.S.B., D.R.B., G.H.W.), and the Thrombosis and Atherosclerosis Research Institute (C.S.M., A.H., A.E., N.S.B., D.R.B., Y.S., G.H.W.), McMaster University, Hamilton, Ontario, Canada.
authors.forename: Cameron S
authors.initials: CS
authors.lastname: McAlpine
authors.affiliation: From the Departments of Medicine (C.S.M., Y.S., G.H.W.), Biochemistry and Biomedical Sciences (N.S.B., D.R.B., G.H.W.), and the Thrombosis and Atherosclerosis Research Institute (C.S.M., A.H., A.E., N.S.B., D.R.B., Y.S., G.H.W.), McMaster University, Hamilton, Ontario, Canada.
authors.forename: Aric
authors.initials: A
authors.lastname: Huang
authors.affiliation: From the Departments of Medicine (C.S.M., Y.S., G.H.W.), Biochemistry and Biomedical Sciences (N.S.B., D.R.B., G.H.W.), and the Thrombosis and Atherosclerosis Research Institute (C.S.M., A.H., A.E., N.S.B., D.R.B., Y.S., G.H.W.), McMaster University, Hamilton, Ontario, Canada.
authors.forename: Abby
authors.initials: A
authors.lastname: Emdin
authors.affiliation: From the Departments of Medicine (C.S.M., Y.S., G.H.W.), Biochemistry and Biomedical Sciences (N.S.B., D.R.B., G.H.W.), and the Thrombosis and Atherosclerosis Research Institute (C.S.M., A.H., A.E., N.S.B., D.R.B., Y.S., G.H.W.), McMaster University, Hamilton, Ontario, Canada.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Banko
authors.affiliation: From the Departments of Medicine (C.S.M., Y.S., G.H.W.), Biochemistry and Biomedical Sciences (N.S.B., D.R.B., G.H.W.), and the Thrombosis and Atherosclerosis Research Institute (C.S.M., A.H., A.E., N.S.B., D.R.B., Y.S., G.H.W.), McMaster University, Hamilton, Ontario, Canada.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Beriault
authors.affiliation: From the Departments of Medicine (C.S.M., Y.S., G.H.W.), Biochemistry and Biomedical Sciences (N.S.B., D.R.B., G.H.W.), and the Thrombosis and Atherosclerosis Research Institute (C.S.M., A.H., A.E., N.S.B., D.R.B., Y.S., G.H.W.), McMaster University, Hamilton, Ontario, Canada.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: From the Departments of Medicine (C.S.M., Y.S., G.H.W.), Biochemistry and Biomedical Sciences (N.S.B., D.R.B., G.H.W.), and the Thrombosis and Atherosclerosis Research Institute (C.S.M., A.H., A.E., N.S.B., D.R.B., Y.S., G.H.W.), McMaster University, Hamilton, Ontario, Canada. Geoff.Werstuck@taari.ca.
authors.forename: Geoff H
authors.initials: GH
authors.lastname: Werstuck
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000503:physiopathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism; D010641:Phenotype
chemical_list: D016207:Cytokines; D038362:Glycogen Synthase Kinase 3
keywords: atherosclerosis; glycogen synthase kinase 3; myeloid cell