Inhibition of myeloperoxidase increases revascularization and improves blood flow in a diabetic mouse model of hindlimb ischaemia.

OBJECTIVE

Diabetes mellitus is a significant risk factor for peripheral artery disease. Diabetes mellitus induces chronic states of oxidative stress and vascular inflammation that increase neutrophil activation and release of myeloperoxidase. The goal of this study is to determine whether inhibiting myeloperoxidase reduces oxidative stress and neutrophil infiltration, increases vascularization, and improves blood flow in a diabetic murine model of hindlimb ischaemia.

METHODS

Leptin receptor-deficient () mice were subjected to hindlimb ischaemia. Ischaemic mice were treated with -acetyl-lysyltyrosylcysteine-amide (KYC) to inhibit myeloperoxidase. After ligating the femoral artery, effects of treatments were determined with respect to hindlimb blood flow, neutrophil infiltration, oxidative damage, and the capability of hindlimb extracellular matrix to support human endothelial cell proliferation and migration.

RESULTS

KYC treatment improved hindlimb blood flow at 7 and 14 days in mice; decreased the formation of advanced glycation end products, 4-hydroxynonenal, and 3-chlorotyrosine; reduced neutrophil infiltration into the hindlimbs; and improved the ability of hindlimb extracellular matrix from mice to support endothelial cell proliferation and migration.

CONCLUSION

These results demonstrate that inhibiting myeloperoxidase reduces oxidative stress in ischaemic hindlimbs of mice, which improves blood flow and reduces neutrophil infiltration such that hindlimb extracellular matrix from mice supports endothelial cell proliferation and migration.