Protein kinase R-like endoplasmic reticulum kinase and glycogen synthase kinase-3α/β regulate foam cell formation

Evidence suggests a causative role for endoplasmic reticulum (ER) stress in the development of atherosclerosis. This study investigated the potential role of glycogen synthase kinase (GSK)-3α/β in proatherogenic ER stress signaling. Thp1-derived macrophages were treated with the ER stress-inducing agents, glucosamine, thapsigargin, or palmitate. Using small-molecule inhibitors of specific unfolded protein response (UPR) signaling pathways, we found that protein kinase R-like ER kinase (PERK), but not inositol requiring enzyme 1 or activating transcription factor 6, is required for the activation of GSK3α/β by ER stress. GSK3α/β inhibition or siRNA-directed knockdown attenuated ER stress-induced expression of distal components of the PERK pathway. Macrophage foam cells within atherosclerotic plaques and isolated macrophages from ApoE−/− mice fed a diet supplemented with the GSK3α/β inhibitor valproate had reduced levels of C/EBP homologous protein (CHOP). GSK3α/β inhibition blocked ER stress-induced lipid accumulation and the upregulation of genes associated with lipid metabolism. In primary mouse macrophages, PERK inhibition blocked ER stress-induced lipid accumulation, whereas constitutively active S9A-GSK3β promoted foam cell formation and CHOP expression, even in cells treated with a PERK inhibitor. These findings suggest that ER stress-PERK-GSK3α/β signaling promotes proatherogenic macrophage lipid accumulation. Evidence suggests a causative role for endoplasmic reticulum (ER) stress in the development of atherosclerosis. This study investigated the potential role of glycogen synthase kinase (GSK)-3α/β in proatherogenic ER stress signaling. Thp1-derived macrophages were treated with the ER stress-inducing agents, glucosamine, thapsigargin, or palmitate. Using small-molecule inhibitors of specific unfolded protein response (UPR) signaling pathways, we found that protein kinase R-like ER kinase (PERK), but not inositol requiring enzyme 1 or activating transcription factor 6, is required for the activation of GSK3α/β by ER stress. GSK3α/β inhibition or siRNA-directed knockdown attenuated ER stress-induced expression of distal components of the PERK pathway. Macrophage foam cells within atherosclerotic plaques and isolated macrophages from ApoE−/− mice fed a diet supplemented with the GSK3α/β inhibitor valproate had reduced levels of C/EBP homologous protein (CHOP). GSK3α/β inhibition blocked ER stress-induced lipid accumulation and the upregulation of genes associated with lipid metabolism. In primary mouse macrophages, PERK inhibition blocked ER stress-induced lipid accumulation, whereas constitutively active S9A-GSK3β promoted foam cell formation and CHOP expression, even in cells treated with a PERK inhibitor. These findings suggest that ER stress-PERK-GSK3α/β signaling promotes proatherogenic macrophage lipid accumulation. Atherosclerosis is an inflammatory disease within the walls of medium and large arteries (1Ross R. Mechanisms of disease - atherosclerosis - an inflammatory disease.N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (19243) Google Scholar). It is the leading cause of cerebrovascular and cardiovascular diseases, which together account for a third of all deaths in Western societies (1Ross R. Mechanisms of disease - atherosclerosis - an inflammatory disease.N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (19243) Google Scholar, 2Glass C.K. Witztum J.L. Atherosclerosis: the road ahead.Cell. 2001; 104: 503-516Abstract Full Text Full Text PDF PubMed Scopus (2636) Google Scholar). Multiple risk factors contribute to the initiation and progression of atherosclerosis including diabetes mellitus, hypertension, obesity, dyslipidemia, a sedentary life style, and smoking (3Yusuf S. Hawken S. Ounpuu S. Dans T. Avezum A. Lanas F. McQueen M. Budaj A. Pais P. Varigos J. INTERHEART Study Investigators et al.Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.Lancet. 2004; 364: 937-952Abstract Full Text Full Text PDF PubMed Scopus (8439) Google Scholar). One of the hallmark features of every stage of atherogenesis, from the fatty streak to the complex plaque, is the presence of lipid-laden macrophages known as foam cells. Intimal macrophage/foam cells accumulate lipids from LDL and modified LDL particles and secrete a variety of inflammatory cytokines. In advanced plaques, foam cells undergo apoptosis, thereby contributing to the formation of a highly thrombotic, lipid rich, necrotic core [reviewed by Moore and Tabas (4Moore K.J. Tabas I. Macrophages in the pathogenesis of atherosclerosis.Cell. 2011; 145: 341-355Abstract Full Text Full Text PDF PubMed Scopus (1814) Google Scholar)]. The molecular events that promote the initiation and development of atherosclerosis are poorly understood. A better understanding of the signaling networks that regulate foam cell formation and atherosclerotic plaque development may lead to the identification of novel therapeutic targets. The endoplasmic reticulum (ER) is the organelle responsible for the proper folding, modification, and processing of secretory, transmembrane, and ER resident proteins. If the processing capacity of the ER is overwhelmed, unfolded or misfolded proteins begin to accumulate, a condition known as ER stress. The accumulation of misfolded proteins triggers the initiation of the unfolded protein response (UPR), which is composed of three signaling cascades regulated by ER transmembrane proteins [reviewed Schroder and Kaufman (5Schröder M. Kaufman R. The mammalian unfolded protein response.Annu. Rev. Biochem. 2005; 74: 739-789Crossref PubMed Scopus (2438) Google Scholar)]. The activation of protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme (IRE) 1, and activating transcription factor (ATF) 6 coordinate the attenuation of protein translation and the increased expression of cellular chaperones, as the cell attempts to reattain ER homeostasis. If these early, adaptive mechanisms are not successful at alleviating the stress, downstream components of the UPR will initiate proapoptotic pathways to eliminate the cell. ER stress and UPR activation have been associated with the progression and development of atherosclerotic plaques. Multiple cardiovascular risk factors including hyperglycemia (6Khan M.I. Pichna B.A. Shi Y. Bowes A.J. Werstuck G.H. Evidence supporting a role for endoplasmic reticulum stress in the development of atherosclerosis in a hyperglycaemic mouse model.Antioxid. Redox Signal. 2009; 11: 2289-2298Crossref PubMed Scopus (55) Google Scholar, 7McAlpine C.S. Bowes A.J. Khan M.I. Shi Y. Werstuck G.H. Endoplasmic reticulum stress and glycogen synthase kinase-3 beta activation in apolipoprotein E-deficient mouse models of accelerated atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2012; 32: 82-91Crossref PubMed Scopus (46) Google Scholar), hyperhomocysteinemia (7McAlpine C.S. Bowes A.J. Khan M.I. Shi Y. Werstuck G.H. Endoplasmic reticulum stress and glycogen synthase kinase-3 beta activation in apolipoprotein E-deficient mouse models of accelerated atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2012; 32: 82-91Crossref PubMed Scopus (46) Google Scholar, 8Werstuck G.H. Lentz S.R. Dayal S. 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Lee Atherosclerosis by a diet is by of expression in PubMed Scopus Google Scholar). the mechanisms by which ER stress and GSK3α/β proatherogenic In we that ER stress-induced GSK3α/β not regulate the adaptive components of UPR signaling but as a of proapoptotic of the PERK signaling pathway. we that inhibition of signaling macrophage lipid and lipid accumulation, and foam cell formation by ER stress. were in medium at and were macrophages by the cells to for macrophages were isolated from mice or ApoE−/− mice and in cells were treated with 1 or with for by the cells with inhibitors and for 2 GSK3α/β with PERK with with 6 and with were to the a of of of an or constitutively active GSK3α/β from and all were or GSK3α/β cells for and as isolated from cells an by the at and by the of the at and from 1 of the 1 and and for and protein were in kinase 1 1 and were in by and to were with primary protein CHOP GSK3α/β or with the primary and were the Western were and to ApoE−/− mice from were a diet and cholesterol 1 of the mice were to an supplemented with valproate the of the mice mice had to and the were at of for atherosclerotic plaque or of for of and and were for The all were and with and with and including the were and in of were were with primary CHOP or were with in of primary to for were with an and a from 6 to mice the of the were and a The of the from to a for are for within the GSK3α/β from cell protein or were from cell protein in kinase a specific for or and A by the of synthase cell or or with and in a 1 and in a of a of were with at were and with and with the by and are and cholesterol levels were in macrophages a to the lipids were from 1 cells with were with a cholesterol and with or cholesterol for at cholesterol levels were by the and cholesterol The of the at and with a known were in the a by cells as and with for 2 at and lipid cells were or and with in by were in were an and a and and a of of these a of were The as as cell were from of a were an cell with a of cells. are cell from at are of at three are as or as to A of cells were macrophages by to for The small-molecule GSK3α/β inhibitor to GSK3α/β J. 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Werstuck G.H. cells from ER stress-induced lipid accumulation and by glycogen synthase 2005; PubMed Scopus Google GSK3α/β inhibition by the accumulation of in cells treated with the of GSK3α/β inhibition ER stress-induced expression, macrophages were for 2 in the presence or of and with ER stress-inducing agents, including 1 or for ER stress GSK3α/β inhibition reduced macrophage cell and The expression levels of the cellular and protein and were These components of the adaptive ER stress response were by and GSK3α/β inhibition not or expression with these siRNA-directed knockdown of GSK3α/β not the of or to protein levels These suggest that GSK3α/β is not required for early, adaptive UPR signaling. investigated the three of UPR and the potential role of GSK3α/β in of these signaling the of ER stress GSK3α/β activation ER stress by and increased GSK3α/β in macrophages Macrophages were to inhibitors of of the three UPR signaling of the but not or attenuated ER stress-induced GSK3α/β and PERK the initiation factor at This in the attenuation of protein translation and the specific upregulation of and of protein from macrophages with or the ER stress-induced of of the activation of the PERK signaling levels were by GSK3α/β inhibition that GSK3α/β not PERK ER stress-induced CHOP and expression were blocked by GSK3α/β inhibition and knockdown and These that GSK3α/β a role in the of downstream components of the PERK of the a role for GSK3α/β in PERK signaling in we CHOP expression in macrophages within the atherosclerotic plaque attenuated by GSK3α/β ApoE−/− mice were an and cholesterol for A of mice were an supplemented with a to GSK3α/β in and in (7McAlpine C.S. Bowes A.J. Khan M.I. Shi Y. Werstuck G.H. Endoplasmic reticulum stress and glycogen synthase kinase-3 beta activation in apolipoprotein E-deficient mouse models of accelerated atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2012; 32: 82-91Crossref PubMed Scopus (46) Google Scholar, A.J. Khan M.I. Shi Y. Werstuck G.H. accelerated atherosclerosis in in of a role for endoplasmic reticulum stress and glycogen synthase kinase-3 in development and J. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, G.H. A.J. T. E. A. the and of valproate and Med. 2004; PubMed Scopus (46) Google Scholar, G. The valproate the of glycogen synthase 1999; PubMed Scopus Google Scholar, P. of and glycogen synthase kinase-3 beta by valproate and PubMed Scopus Google Scholar). have that ApoE−/− mice fed an supplemented with with attenuated in and within the and have reduced atherosclerotic plaque and necrotic core (7McAlpine C.S. Bowes A.J. Khan M.I. Shi Y. Werstuck G.H. Endoplasmic reticulum stress and glycogen synthase kinase-3 beta activation in apolipoprotein E-deficient mouse models of accelerated atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2012; 32: 82-91Crossref PubMed Scopus (46) Google Scholar). were with a and an specific for and were with to for and to or in the were with and a in CHOP within macrophages of the atherosclerotic plaque in mice of ApoE−/− mice an with and to mice fed the core to mice fed the to mice fed the in a expression is reduced in macrophages from ApoE−/− mice supplemented with from ApoE−/− mice fed an with or with the GSK3α/β inhibitor as were with and and or and CHOP are the of and CHOP macrophages were isolated from ApoE−/− mice fed an or an supplemented with isolated from macrophages, and the expression levels of and CHOP were by cell protein from macrophages were by and with and and were by to macrophages were isolated from a of ApoE−/− mice fed an or an supplemented with for Macrophages isolated from mice fed an supplemented with reduced CHOP protein and expression, and and protein levels were to mice These are with in that GSK3α/β not regulate adaptive components of the UPR but distal components of the PERK signaling pathway. that ER stress may a role in the accumulation of lipids in atherosclerotic foam cells. suggest that inhibition of GSK3α/β will macrophages were with ER stress-inducing in the presence or of the expression levels of in lipid and were by that ER stress associated with expression of genes lipid and cholesterol including and LDL of GSK3α/β by attenuated ER stress-induced and expression levels of genes in pathways were not by ER stress or GSK3α/β inhibition these in expression lipid and cholesterol accumulation within macrophages, and cholesterol levels were ER stress by and in accumulation of and cholesterol GSK3α/β inhibition by as as GSK3α/β attenuated the accumulation of and cholesterol in the and with these increased lipid formation in the macrophages to ER stress-inducing agents, and siRNA-directed GSK3α/β knockdown attenuated The by which ER stress signaling GSK3α/β promotes macrophage lipid accumulation and foam cell formation lipid ER stress signaling GSK3α/β a role in of modified macrophages were with LDL with with ER stress-inducing and blocked by GSK3α/β inhibition the lipid macrophages were treated with ER stress-inducing and in the of ER stress cellular cholesterol and attenuated by GSK3α/β inhibition ER stress GSK3α/β inhibition macrophage these suggest that ER stress signaling GSK3α/β a role in lipid and the of signaling in primary macrophages, macrophages were isolated from macrophages were in the presence or of ER stress-inducing agents, or with findings in ER stress increased lipid as by to of PERK or GSK3α/β to ER stress-induced lipid accumulation, and cells treated with of these inhibitors had lipid to in cells signaling foam cell formation in primary mouse mouse macrophages were isolated from Macrophages were to 1 or in the presence or of PERK inhibitor or cells were with and are and mouse macrophages were with constitutively active or an ER stress in the cells as in the presence or of or PERK inhibitor. were with and are and from primary macrophages with or to PERK inhibitor were by and for CHOP and are and CHOP expression by in primary macrophages S9A-GSK3β in the presence or of PERK inhibitor to to cells of the signaling foam cell formation in primary mouse mouse macrophages were isolated from Macrophages were to 1 or in the presence or of PERK inhibitor or cells were with and are and mouse macrophages were with constitutively active or an ER stress in the cells as in the presence or of or PERK inhibitor. were with and are and from primary macrophages with or to PERK inhibitor were by and for CHOP and are and CHOP expression by in primary macrophages S9A-GSK3β in the presence or of PERK inhibitor to to cells of the A constitutively active of in primary macrophages an of a cells were with an of S9A-GSK3β in lipid accumulation, which not by the presence or of ER stress PERK which blocked ER stress-induced lipid accumulation not the of to macrophage lipid the cells to attenuated lipid accumulation activation in the of CHOP protein levels and expression in primary macrophages, even in the presence of the PERK inhibitor these are with that ER stress to macrophage lipid accumulation and foam cell suggests a causative role for ER stress in the and progression of atherosclerosis (7McAlpine C.S. Bowes A.J. Khan M.I. Shi Y. Werstuck G.H. Endoplasmic reticulum stress and glycogen synthase kinase-3 beta activation in apolipoprotein E-deficient mouse models of accelerated atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2012; 32: 82-91Crossref PubMed Scopus (46) Google Scholar, M. E. endoplasmic reticulum stress unfolded protein response in in of to 2009; PubMed Scopus Google Scholar, J. S. B.A. of the unfolded protein response at all of atherosclerotic development in apolipoprotein E-deficient 2005; PubMed Scopus Google Scholar, A.J. Khan M.I. Shi Y. Werstuck G.H. accelerated atherosclerosis in in of a role for endoplasmic reticulum stress and glycogen synthase kinase-3 in development and J. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). The of ER stress the proatherogenic are poorly understood. that the PERK of the UPR GSK3α/β to promote macrophage foam cell suggest that GSK3α/β not the adaptive components of ER stress signaling including expression and translation attenuation in ER stress-induced GSK3α/β activation a role in the distal components of the PERK and is in the upregulation of transcription factors including and or knockdown of PERK or GSK3α/β ER stress-induced macrophage lipid accumulation. suggest that lipid and pathways may is that lipid from macrophages is regulated by GSK3α/β U. mechanisms responsible for the reduced expression of cholesterol from macrophages by Thromb. Vasc. Biol. PubMed Scopus Google Scholar). activation is to the of PERK inhibition and promotes lipid accumulation and foam cell activation CHOP protein and expression even PERK is these a novel signaling by which ER stress may promote lipid accumulation in macrophage foam cells by activation of the pathway. Multiple cardiovascular risk factors are of ER stress in cell and the mechanisms by which risk factors promote ER stress are not understood. levels of ER stress have been in models of obesity, and (6Khan M.I. Pichna B.A. Shi Y. Bowes A.J. Werstuck G.H. Evidence supporting a role for endoplasmic reticulum stress in the development of atherosclerosis in a hyperglycaemic mouse model.Antioxid. Redox Signal. 2009; 11: 2289-2298Crossref PubMed Scopus (55) Google Scholar, 7McAlpine C.S. Bowes A.J. Khan M.I. Shi Y. Werstuck G.H. Endoplasmic reticulum stress and glycogen synthase kinase-3 beta activation in apolipoprotein E-deficient mouse models of accelerated atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2012; 32: 82-91Crossref PubMed Scopus (46) Google Scholar, A.J. Khan M.I. Shi Y. Werstuck G.H. accelerated atherosclerosis in in of a role for endoplasmic reticulum stress and glycogen synthase kinase-3 in development and J. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, U. mechanisms responsible for the reduced expression of cholesterol from macrophages by Thromb. Vasc. Biol. PubMed Scopus Google Scholar, A. M. S. A.J. et of ER stress and levels in Clin. Invest. 2012; PubMed Scopus Google Scholar). In a a of within cells and as a of ER stress C. M. F. M. R. P. et endoplasmic reticulum stress expression activating transcription factor 6 in and PubMed Scopus Google Scholar, Shi Y. Khan M.I. A. Werstuck G.H. promotes endoplasmic reticulum stress, lipid accumulation, and inflammatory expression in J. PubMed Scopus Google Scholar, S. Shi Y. Khan M.I. Werstuck G.H. promotes endoplasmic reticulum stress, and accelerated in ApoE−/− 2011; Full Text Full Text PDF PubMed Scopus Google Scholar). In lipids as and cholesterol are to ER by the of the ER Y. T. R. Tabas I. macrophages are an of and of and in advanced Biol. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. endoplasmic reticulum stress, and causes in mouse and primary J. PubMed Scopus Google Scholar). ER activation may a by which cardiovascular risk factors promote atherosclerosis GSK3α/β is in a of signaling and of cell and The role of GSK3α/β in the of inflammatory is in and macrophages, of is by GSK3α/β synthase kinase beta to Biol. 2005; PubMed Scopus Google Scholar). GSK3α/β to a role in the of expression, an In and macrophages, of the kinase in of and in a in expression M. R. S. is regulated by glycogen synthase kinase 2005; PubMed Scopus Google Scholar, G. S. of is promoted by the kinase PubMed Scopus Google Scholar). GSK3α/β inhibition may the expression of the and M. R. S. is regulated by glycogen synthase kinase 2005; PubMed Scopus Google Scholar). the of we the of a role for GSK3α/β in the of lipid in these findings may that GSK3α/β a role in the foam cells and The of ER stress signaling in disease been and the PERK signaling of the UPR been the of In the and CHOP atherosclerotic plaque and plaque E. G. G. Tabas I. and plaque in advanced atherosclerotic of and mice 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). and mice fed a Western diet atherosclerotic plaques that are necrotic and activation E. G. G. Tabas I. and plaque in advanced atherosclerotic of and mice 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). et S. Y. M. of translation initiation factor 2 and in Full Text Full Text PDF PubMed Scopus Google a mouse in which by and protein These mice had signaling the downstream components of the PERK and reduced and triglyceride as as and insulin E. G. G. Tabas I. and plaque in advanced atherosclerotic of and mice 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). The these mice by reduced expression of genes in lipid including and S. Y. M. of translation initiation factor 2 and in Full Text Full Text PDF PubMed Scopus Google Scholar). mice have and with and reduced and expression C. Y. Y. S. F. lipid and PubMed Scopus Google Scholar). that the and pathways are not in ER stress signaling have that the and a role in the of lipid A.H. Glimcher L.H. of by the transcription factor PubMed Scopus Google Scholar, J. Lee Lee J. and contribute to in C. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. T. A. of and lipid formation in mice with endoplasmic reticulum Biol. PubMed Scopus Google Scholar). poorly UPR pathways to coordinate the response to an and these pathways may regulate lipid A.H. Glimcher L.H. of the unfolded protein response and lipid 2009; PubMed Scopus Google Scholar). These with the suggest that activation of the PERK of the UPR to increased lipid and attenuation of PERK signaling lipid an role for GSK3α/β in the of downstream components of the PERK signaling of the signaling may a role in the of macrophage lipid accumulation and foam cell formation in are a of of that to will to the by which PERK GSK3α/β and signaling networks as the or pathways are we to the of GSK3α/β and in the of and CHOP expression, as as lipid metabolism. This will a of the of GSK3α/β that have been S. P. stage J. 2001; PubMed Scopus Google Scholar). It will to the specific of and in The of these pathways may lead to the identification of novel for the development of an a understanding of the mechanisms ER stress and proatherogenic with LDL activating transcription factor protein homologous protein initiation factor endoplasmic reticulum protein glycogen synthase kinase diet inositol requiring enzyme LDL of factor protein endoplasmic reticulum kinase protein unfolded protein response valproate

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