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Pkr‐like endoplasmic reticulum kinase (PERK) and glycogen synthase kinase‐3α/β signaling regulate atherosclerosis development (278.5)
Author(s) -
McAlpine Cameron,
Werstuck Geoff
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.278.5
Subject(s) - unfolded protein response , gsk 3 , atf6 , endoplasmic reticulum , thapsigargin , gsk3b , microbiology and biotechnology , kinase , signal transduction , protein kinase r , glycogen synthase , chemistry , biology , protein kinase a , phosphorylation , mitogen activated protein kinase kinase
Recently, a role for endoplasmic reticulum (ER) stress signaling through glycogen synthase kinase (GSK)‐3α/β has been proposed in atherogenesis; this study sought to delineate the underlying molecular mechanisms. Cultured THP1‐derived macrophages were treated with the ER stress‐inducing agents, glucosamine, thapsigargin or palmitate in the presence or absence of inhibitors of the unfolded protein response (UPR) pathways (PERK, IRE, ATF6) or GSK3α/β (CT99021). ER stress enhanced GSK3α/β activity while inhibition of the PERK pathway, but not the IRE or ATF6 pathways, attenuated GSK3α/β activity. GSK3α/β inhibition did not affect adaptive components of the UPR but did repress the expression of factors downstream of PERK (ATF4 and CHOP). ER stress enhanced the mRNA expression of genes controlling lipid biosynthesis and uptake; while GSK3α/β inhibition attenuated this effect. GSK3α/β inhibition blocked ER stress‐induced cholesterol accumulation in macrophages. To investigate the roles of macrophage GSK3α and GSK3β in a mouse model of atherosclerosis, LDLR‐/‐ myeloid cell GSK3α knockout (LDLR‐/‐GSK3αflox/floxLyzMCre+/‐) and GSK3β knockout (LDLR‐/‐GSK3βflox/floxLyzMCre+/‐) mice were placed on a high fat diet. Myeloid cell GSK3α deficiency, but not GSK3β deficiency, attenuated atherogenesis. Our findings support a role for macrophage PERK ‐ GSK3α signaling in atherosclerosis development.