title: Glyoxalase-1 overexpression in bone marrow cells reverses defective neovascularization in STZ-induced diabetic mice.
abstract: OBJECTIVE
  Methylglyoxal (MG) accumulates in diabetes and impairs neovascularization. This study assessed whether overexpressing the MG-metabolizing enzyme glyoxalase-1 (GLO1) in only bone marrow cells (BMCs) could restore neovascularization in ischaemic tissue of streptozotocin-induced diabetic mice.
  
  
  RESULTS
  After 24 h of hyperglycaemic and hypoxic culture, BMCs from GLO1 overexpressing and wild-type (WT) diabetic mice were compared for migratory potential, viability, and mRNA expression of anti-apoptotic genes (Bcl-2 and Bcl-XL). In vivo, BMCs from enhanced green fluorescent protein (eGFP) mice that overexpress GLO1 were used to reconstitute the BM of diabetic mice (GLO1-diabetics). Diabetic and non-diabetic recipients of WT GFP(+) BM served as controls (WT-diabetics and non-diabetics, respectively). Following hindlimb ischaemia, the mobilization of BMCs was measured by flow cytometry. In hindlimbs, the presence of BM-derived angiogenic (GFP(+)CXCR4(+)) and endothelial (GFP(+)vWF(+)) cells and also arteriole density were determined by immunohistochemistry. Hindlimb perfusion was measured using laser Doppler. GLO1-BMCs had superior migratory potential, increased viability, and greater Bcl-2 and Bcl-XL expression, compared with WT BMCs. In vivo, the mobilization of pro-angiogenic BMCs (CXCR4(+), c-kit(+), and Flk(+)) was enhanced post-ischaemia in GLO1-diabetics compared to WT-diabetics. A greater number of GFP(+)CXCR4(+) and GFP(+)vWF(+) BMCs incorporated into the hindlimb tissue of GLO1-diabetics and non-diabetics than in WT-diabetics. Arteriole and capillary density and perfusion were also greater in GLO1-diabetics and non-diabetics.
  
  
  CONCLUSIONS
  This study demonstrates that protection from MG uniquely in BM is sufficient to restore BMC function and neovascularization of ischaemic tissue in diabetes and identifies GLO1 as a potential therapeutic target.
authors.affiliation: Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, Canada K1Y 4W7.
authors.forename: Branka
authors.initials: B
authors.lastname: Vulesevic
authors.forename: Brian
authors.initials: B
authors.lastname: McNeill
authors.forename: Michele
authors.initials: M
authors.lastname: Geoffrion
authors.forename: Drew
authors.initials: D
authors.lastname: Kuraitis
authors.forename: Joanne E
authors.initials: JE
authors.lastname: McBane
authors.forename: Marina
authors.initials: M
authors.lastname: Lochhead
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Vanderhyden
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Korbutt
authors.forename: Ross W
authors.initials: RW
authors.lastname: Milne
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Suuronen
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism; D001854:Bone Marrow Cells / Q000201:enzymology*; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000601:surgery*; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000601:surgery*; D003925:Diabetic Angiopathies / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000601:surgery*; D006614:Hindlimb; D006801:Humans; D007511:Ischemia / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000601:surgery*; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000473:pathology; D009389:Neovascularization, Pathologic; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011765:Pyruvaldehyde / Q000378:metabolism; D020127:Recovery of Function; D012039:Regional Blood Flow; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D042501:Angiogenic Proteins; D001786:Blood Glucose; D016207:Cytokines; D011765:Pyruvaldehyde; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D007791:Lactoylglutathione Lyase
keywords: Bone marrow cells; Methylglyoxal; Neovascularization; Type 1 diabetes