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10.1161/ATVBAHA.114.304454

http://scihub22266oqcxt.onion/10.1161/ATVBAHA.114.304454
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25614279!ä!25614279

suck abstract from ncbi


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pmid25614279      Arterioscler+Thromb+Vasc+Biol 2015 ; 35 (3): 547-57
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  • Pivotal role of serum- and glucocorticoid-inducible kinase 1 in vascular inflammation and atherogenesis #MMPMID25614279
  • Borst O; Schaub M; Walker B; Schmid E; Munzer P; Voelkl J; Alesutan I; Rodriguez JM; Vogel S; Schoenberger T; Metzger K; Rath D; Umbach A; Kuhl D; Muller II; Seizer P; Geisler T; Gawaz M; Lang F
  • Arterioscler Thromb Vasc Biol 2015[Mar]; 35 (3): 547-57 PMID25614279show ga
  • OBJECTIVE: Atherosclerosis, an inflammatory disease of arterial vessel walls, requires migration and matrix metalloproteinase (MMP)-9-dependent invasion of monocytes/macrophages into the vascular wall. MMP-9 expression is stimulated by transcription factor nuclear factor-kappaB, which is regulated by inhibitor kappaB (IkappaB) and thus IkappaB kinase. Regulators of nuclear factor-kappaB include serum- and glucocorticoid-inducible kinase 1 (SGK1). The present study explored involvement of SGK1 in vascular inflammation and atherogenesis. APPROACH AND RESULTS: Gene-targeted apolipoprotein E (ApoE)-deficient mice without (apoe(-/-)sgk1(+/+)) or with (apoe(-/-)sgk1(-/-)) additional SGK1 knockout received 16-week cholesterol-rich diet. According to immunohistochemistry atherosclerotic lesions in aorta and carotid artery, vascular CD45(+) leukocyte infiltration, Mac-3(+) macrophage infiltration, vascular smooth muscle cell content, MMP-2, and MMP-9 positive areas in atherosclerotic tissue were significantly less in apoe(-/-)sgk1(-/-)mice than in apoe(-/-)sgk1(+/+)mice. As determined by Boyden chamber, thioglycollate-induced peritonitis and air pouch model, migration of SGK1-deficient CD11b(+)F4/80(+) macrophages was significantly diminished in vitro and in vivo. Zymographic MMP-2 and MMP-9 production, MMP-9 activity and invasion through matrigel in vitro were significantly less in sgk1(-/-) than in sgk1(+/+)macrophages and in control plasmid-transfected or inactive (K127N)SGK1-transfected than in constitutively active (S422D)SGK1-transfected THP-1 cells. Confocal microscopy revealed reduced macrophage number and macrophage MMP-9 content in plaques of apoe(-/-)sgk1(-/-) mice. In THP-1 cells, MMP-inhibitor GM6001 (25 mumol/L) abrogated (S422D)SGK1-induced MMP-9 production and invasion. According to reverse transcription polymerase chain reaction, MMP-9 transcript levels were significantly reduced in sgk1(-/-)macrophages and strongly upregulated in (S422D)SGK1-transfected THP-1 cells compared with control plasmid-transfected or (K127N)SGK1-transfected THP-1 cells. According to immunoblotting and confocal microscopy, phosphorylation of IkappaB kinase and inhibitor kappaB and nuclear translocation of p50 were significantly lower in sgk1(-/-)macrophages than in sgk1(+/+)macrophages and significantly higher in (S422D)SGK1-transfected THP-1 cells than in control plasmid-transfected or (K127N)SGK1-transfected THP-1 cells. Treatment of (S422D)SGK1-transfected THP-1 cells with IkappaB kinase-inhibitor BMS-345541 (10 mumol/L) abolished (S422D)SGK1-induced increase of MMP-9 transcription and gelatinase activity. CONCLUSIONS: SGK1 plays a pivotal role in vascular inflammation during atherogenesis. SGK1 participates in the regulation of monocyte/macrophage migration and MMP-9 transcription via regulation of nuclear factor-kappaB.
  • |*Chemotaxis[MESH]
  • |Active Transport, Cell Nucleus[MESH]
  • |Animals[MESH]
  • |Aorta/enzymology/pathology[MESH]
  • |Aortic Diseases/*enzymology/genetics/pathology[MESH]
  • |Apolipoproteins E/deficiency/genetics[MESH]
  • |Atherosclerosis/*enzymology/genetics/pathology[MESH]
  • |Carotid Arteries/enzymology/pathology[MESH]
  • |Carotid Artery Diseases/*enzymology/genetics/pathology[MESH]
  • |Cell Line[MESH]
  • |Disease Models, Animal[MESH]
  • |Gene Expression Regulation, Enzymologic[MESH]
  • |Humans[MESH]
  • |I-kappa B Kinase/metabolism[MESH]
  • |I-kappa B Proteins/metabolism[MESH]
  • |Immediate-Early Proteins/deficiency/genetics/*metabolism[MESH]
  • |Inflammation/*enzymology/genetics/pathology[MESH]
  • |Macrophages/enzymology/pathology[MESH]
  • |Male[MESH]
  • |Matrix Metalloproteinase 2/metabolism[MESH]
  • |Matrix Metalloproteinase 9/genetics/metabolism[MESH]
  • |Mice, Inbred C57BL[MESH]
  • |Mice, Knockout[MESH]
  • |Mutation[MESH]
  • |NF-kappa B p50 Subunit/metabolism[MESH]
  • |Peritonitis/chemically induced/enzymology/genetics[MESH]
  • |Plaque, Atherosclerotic[MESH]
  • |Protein Serine-Threonine Kinases/deficiency/genetics/*metabolism[MESH]
  • |Signal Transduction[MESH]
  • |Thioglycolates[MESH]
  • |Transcription, Genetic[MESH]
  • |Transfection[MESH]


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