title: Hyperglycemia Suppresses Calcium Phosphate-Induced Aneurysm Formation Through Inhibition of Macrophage Activation.
abstract: BACKGROUND
  The aim of this study was to elucidate aspects of diabetes mellitus-induced suppression of aneurysm. We hypothesized that high glucose suppresses aneurysm by inhibiting macrophage activation via activation of Nr1h2 (also known as liver X receptor β), recently characterized as a glucose-sensing nuclear receptor.
  
  
  RESULTS
  Calcium phosphate (CaPO4)-induced aneurysm formation was significantly suppressed in the arterial wall in type 1 and 2 diabetic mice. A murine macrophage cell line, RAW264.7, was treated with tumor necrosis factor α (TNF-α) plus CaPO4 and showed a significant increase in matrix metalloproteinase 9 (Mmp9) mRNA and secreted protein expression compared with TNF-α alone. Elevated Mmp9 expression was significantly suppressed by hyperglycemic conditions (15.5 mmol/L glucose) compared with normoglycemic conditions (5.5 mmol/L glucose) or normoglycemic conditions with high osmotic pressure (5.5 mmol/L glucose +10.0 mmol/L mannitol). Nr1h2 mRNA and protein expression were suppressed by treatment with TNF-α plus CaPO4 but were restored by hyperglycemic conditions. Activation of Nr1h2 by the antagonist GW3965 during stimulation with TNF-α plus CaPO4 mimicked hyperglycemic conditions and inhibited Mmp9 upregulation, whereas the deactivation of Nr1h2 by small interfering RNA (siRNA) under hyperglycemic conditions canceled the suppressive effect and restored Mmp9 expression induced by TNF-α plus CaPO4. Moreover, Nr1h2 activation with GW3965 significantly suppressed CaPO4-induced aneurysm in mice compared with vehicle-injected control mice.
  
  
  CONCLUSIONS
  Our results show that hyperglycemia suppresses macrophage activation and aneurysmal degeneration through the activation of Nr1h2. Although further validation of the underlying pathway is necessary, targeting Nr1h2 is a potential therapeutic approach to treating aneurysm.
authors.affiliation: Division of Vascular Surgery, Department of Surgery, Wisconsin Institute for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI.
authors.forename: Teruyoshi
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Division of Vascular Surgery, Department of Surgery, Wisconsin Institute for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Takei
authors.affiliation: Division of Vascular Surgery, Department of Surgery, Wisconsin Institute for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI yamano@surgery.wisc.edu.
authors.forename: Dai
authors.initials: D
authors.lastname: Yamanouchi
mesh_terms: D000783:Aneurysm / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D002130:Calcium Phosphates; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002340:Carotid Artery Diseases / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000139:chemically induced / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000139:chemically induced / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics; D000071518:Liver X Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D015398:Signal Transduction; D013311:Streptozocin; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D001565:Benzoates; D001596:Benzylamines; D015415:Biomarkers; D001786:Blood Glucose; D002130:Calcium Phosphates; C473027:GW 3965; D000071518:Liver X Receptors; C000605211:Nr1h2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D013311:Streptozocin; C020243:calcium phosphate; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: LXRβ; Nr1h2; aneurysm; diabetes mellitus; macrophage activation; metalloproteinases