Glyoxalase-1 over-expression in bone marrow cells reverses defective neovascularization in STZ-induced diabetic mice.

Cardiovascular Research

PubMedID: 24259499

Vulesevic B, McNeill B, Geoffrion M, Kuraitis D, McBane JE, Lochhead M, Vanderhyden BC, Korbutt GS, Milne RW, Suuronen EJ. Glyoxalase-1 over-expression in bone marrow cells reverses defective neovascularization in STZ-induced diabetic mice. Cardiovasc Res. 2014;101(2):306-16.
AIMS
Methylglyoxal accumulates in diabetes and impairs neovascularization. This study assessed whether over-expressing the methylglyoxal-metabolizing enzyme glyoxalase-1 (GLO1) in only bone marrow cells (BMCs) could restore neovascularization in ischemic tissue of streptozotocin-induced diabetic mice.Methods and ResultsAfter 24 h of hyperglycemic and hypoxic culture, BMCs from GLO1 over-expressing 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 (GFP) mice that over-express 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 ischemia, 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 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 to WT BMCs. In vivo, the mobilization of pro-angiogenic BMCs (CXCR4(+), c-kit(+) and Flk(+)) was enhanced post-ischemia in GLO1-diabetics compared to WT-diabetics. A greater number of GFP(+)CXCR4(+) and GFP(+)vWF(+) BMCs incorporated into 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 methylglyoxal uniquely in BM is sufficient to restore BMC function and neovascularization of ischemic tissue in diabetes and identifies GLO1 as a potential therapeutic target.