Glyoxalase-1 overexpression in bone marrow cells reverses defective neovascularization in STZ-induced diabetic mice

Cardiovasc Res. 2014 Feb 1;101(2):306-16. doi: 10.1093/cvr/cvt259. Epub 2013 Nov 20.


Aims: 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.

Methods and 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.

Conclusion: 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.

Keywords: Bone marrow cells; Methylglyoxal; Neovascularization; Type 1 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenic Proteins / genetics
  • Angiogenic Proteins / metabolism
  • Animals
  • Apoptosis
  • Blood Glucose / metabolism
  • Bone Marrow Cells / enzymology*
  • Bone Marrow Transplantation*
  • Cell Movement
  • Cell Survival
  • Cells, Cultured
  • Cytokines / metabolism
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetes Mellitus, Experimental / surgery*
  • Diabetes Mellitus, Type 1 / enzymology
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / physiopathology
  • Diabetes Mellitus, Type 1 / surgery*
  • Diabetic Angiopathies / enzymology
  • Diabetic Angiopathies / genetics
  • Diabetic Angiopathies / physiopathology
  • Diabetic Angiopathies / surgery*
  • Hindlimb
  • Humans
  • Ischemia / enzymology
  • Ischemia / genetics
  • Ischemia / physiopathology
  • Ischemia / surgery*
  • Lactoylglutathione Lyase / genetics
  • Lactoylglutathione Lyase / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle, Skeletal / blood supply*
  • Muscle, Skeletal / pathology
  • Neovascularization, Pathologic*
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism
  • Oxidation-Reduction
  • Oxidative Stress
  • Pyruvaldehyde / metabolism
  • Recovery of Function
  • Regional Blood Flow
  • Time Factors
  • Up-Regulation


  • Angiogenic Proteins
  • Blood Glucose
  • Cytokines
  • Pyruvaldehyde
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Lactoylglutathione Lyase