title: Glyoxalase 1 overexpression does not affect atherosclerotic lesion size and severity in ApoE-/- mice with or without diabetes.
abstract: OBJECTIVE
  Advanced glycation end-products (AGEs) and their precursors have been associated with the development of atherosclerosis. We recently discovered that glyoxalase 1 (GLO1), the major detoxifying enzyme for AGE precursors, is decreased in ruptured human plaques, and that levels of AGEs are higher in rupture-prone plaques. We here investigated whether overexpression of human GLO1 in ApoE(-/-) mice could reduce the development of atherosclerosis.
  
  
  RESULTS
  We crossed C57BL/6 ApoE(-/-) mice with C57BL/6 GLO1 overexpressing mice (huGLO1(+/-)) to generate ApoE(-/-) (n = 16) and ApoE(-/-) huGLO1(+/-) (n = 20) mice. To induce diabetes, we injected a subset with streptozotocin (STZ) to generate diabetic ApoE(-/-) (n = 8) and ApoE(-/-) huGLO1(+/-) (n = 13) mice. All mice were fed chow and sacrificed at 25 weeks of age. The GLO1 activity was three-fold increased in huGLO1(+/-) aorta, but aortic root lesion size and phenotype did not differ between mice with and without huGLO1(+/-) overexpression. We detected no differences in gene expression in aortic arches, in AGE levels and cytokines, in circulating cells, and endothelial function between ApoE(-/-) mice with and without huGLO1(+/-) overexpression. Although diabetic mice showed decreased GLO1 expression (P < 0.05) and increased lesion size (P < 0.05) in comparison with non-diabetic mice, GLO1 overexpression also did not affect the aortic root lesion size or inflammation in diabetic mice.
  
  
  CONCLUSIONS
  In ApoE(-/-) mice with or without diabetes, GLO1 overexpression did not lead to decreased atherosclerotic lesion size or systemic inflammation. Increasing GLO1 levels does not seem to be an effective strategy to reduce glycation in atherosclerotic lesions, likely due to increased AGE formation through GLO1-independent mechanisms.
authors.affiliation: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands Department of Internal Medicine, Laboratory for Metabolism and Vascular Medicine, MUMC, Debeyelaan 25, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
authors.forename: Nordin M J
authors.initials: NM
authors.lastname: Hanssen
authors.affiliation: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands Department of Internal Medicine, Laboratory for Metabolism and Vascular Medicine, MUMC, Debeyelaan 25, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
authors.forename: Olaf
authors.initials: O
authors.lastname: Brouwers
authors.affiliation: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands Department of Pathology, MUMC, Maastricht, The Netherlands Department of Molecular Genetics, MUMC, Maastricht, The Netherlands Department of Medical Biochemistry, Amsterdam Medical Centre, Amsterdam, The Netherlands.
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Gijbels
authors.affiliation: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands Department of Internal Medicine, Laboratory for Metabolism and Vascular Medicine, MUMC, Debeyelaan 25, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
authors.forename: Kristiaan
authors.initials: K
authors.lastname: Wouters
authors.affiliation: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands Department of Pathology, MUMC, Maastricht, The Netherlands.
authors.forename: Erwin
authors.initials: E
authors.lastname: Wijnands
authors.affiliation: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands Department of Pathology, MUMC, Maastricht, The Netherlands.
authors.forename: Jack P M
authors.initials: JP
authors.lastname: Cleutjens
authors.affiliation: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Jo G
authors.initials: JG
authors.lastname: De Mey
authors.affiliation: United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.affiliation: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands Department of Pathology, MUMC, Maastricht, The Netherlands.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Biessen
authors.affiliation: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands Department of Internal Medicine, Laboratory for Metabolism and Vascular Medicine, MUMC, Debeyelaan 25, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
authors.forename: Coen D A
authors.initials: CD
authors.lastname: Stehouwer
authors.affiliation: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands Department of Internal Medicine, Laboratory for Metabolism and Vascular Medicine, MUMC, Debeyelaan 25, PO Box 5800, 6202 AZ Maastricht, The Netherlands c.schalkwijk@maastrichtuniversity.nl.
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D001018:Aortic Diseases / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001057:Apolipoproteins E; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000503:physiopathology; D017127:Glycation End Products, Advanced / Q000097:blood; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018384:Oxidative Stress; D058226:Plaque, Atherosclerotic; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D013311:Streptozocin; D015854:Up-Regulation
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D017127:Glycation End Products, Advanced; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D013311:Streptozocin; C000597196:GLO1 protein, human; D007791:Lactoylglutathione Lyase
keywords: Advanced glycation end-products; Atherosclerosis; Diabetes