title: Oxidized LDL-Exposed Human Macrophages Display Increased MMP-9 Expression and Secretion Mediated by Endoplasmic Reticulum Stress.
abstract: Oxidatively modified low-density lipoproteins (oxLDL) alter the proper function of the endoplasmic reticulum (ER), inducing ER stress (ERS), which consequently activates inflammatory pathways in macrophages. Matrix metalloproteinase-9 (MMP-9) is the main protease acting on the degradation of the extracellular matrix and the ensuing destabilization of the atherosclerotic plaque. We aimed to investigate whether ERS induced by oxLDL or tunicamycin (TM) in human macrophages is associated with the stimulation of MMP-9 expression and secretion. The results showed that oxLDL induced in THP-1 macrophages: (i) increase of MMP-9 gene expression and its pro-form secretion, (ii) intracellular accumulation of 7-ketocholesterol, (iii) ERS activation (increased eIF2α phosphorylation, XBP1 and CHOP mRNA levels, and Grp78 protein expression), and (iv) oxidative stress (increased levels of reactive oxygen species and NADPH oxidase activity). Incubation of macrophages with ERS inducer, TM determined the secretion of both pro- and active-form of MMP-9 and oxidative stress. Treatment of oxLDL or TM-incubated cells with ERS inhibitor, sodium phenylbutyrate decreased MMP-9 gene expression, secretion, and activity. The inhibitor of NADPH oxidase, apocynin, decreased XBP-1 and CHOP mRNA levels, and MMP-9 gene expression and secretion in oxLDL-exposed cells. In conclusion, oxLDL stimulate MMP-9 expression and secretion in human macrophages by mechanisms involving ERS. J. Cell. Biochem. 118: 661-669, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8, B.P. Hasdeu Street, Bucharest, 050568, Romania.
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Sanda
authors.affiliation: Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8, B.P. Hasdeu Street, Bucharest, 050568, Romania.|Faculty of Biotechnology, University of Agronomical Sciences and Veterinary Medicine, Bucharest, Romania.
authors.forename: Mariana
authors.initials: M
authors.lastname: Deleanu
authors.affiliation: Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8, B.P. Hasdeu Street, Bucharest, 050568, Romania.
authors.forename: Laura
authors.initials: L
authors.lastname: Toma
authors.affiliation: Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8, B.P. Hasdeu Street, Bucharest, 050568, Romania.
authors.forename: Camelia S
authors.initials: CS
authors.lastname: Stancu
authors.affiliation: Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8, B.P. Hasdeu Street, Bucharest, 050568, Romania.
authors.forename: Maya
authors.initials: M
authors.lastname: Simionescu
authors.affiliation: Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8, B.P. Hasdeu Street, Bucharest, 050568, Romania.
authors.forename: Anca V
authors.initials: AV
authors.lastname: Sima
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007653:Ketocholesterols / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000633:toxicity
chemical_list: D000098:Acetophenones; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; C000717247:HSPA5 protein, human; D007653:Ketocholesterols; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C099252:oxidized low density lipoprotein; D014415:Tunicamycin; C056165:acetovanillone; D019255:NADPH Oxidases; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C003001:7-ketocholesterol
keywords: ENDOPLASMIC RETICULUM STRESS; MACROPHAGES; MATRIX METALLOPROTEINASE; OXIDIZED LDL; TUNICAMYCIN