Abstract
Background. The role of the receptor for advanced glycation end products (RAGE) for the impaired angiogenic response in diabetic patients is not well known. We investigated the impact of RAGE suppression by soluble RAGE (sRAGE) on the angiogenic response in a diabetic hindlimb ischemia mouse model. Materials and Methods. Hindlimb ischemia model was prepared by ligation of femoral artery in diabetic and nondiabetic mice. Ischemia-induced angiogenic response was evaluated by laser-Doppler perfusion imaging, muscle capillary density, and protein expression of vascular endothelial growth factor (VEGF) and high-mobility group box (HMGB)-1. Results. Diabetic mice showed attenuated recovery of ischemic limb perfusion on laser-Doppler perfusion imaging compared with nondiabetic mice. The treatment with sRAGE significantly improved blood flow in the ischemic limbs of diabetic mice. The expression levels of VEGF and HMGB-1 in the limb muscle tissues of diabetic mice were lower than in those of nondiabetic mice. The treatment with sRAGE significantly increased the VEGF and HMGB-1 protein expression in the ischemic limb muscle tissues in the diabetic mice. Conclusion. The suppression of RAGE by sRAGE administration improved angiogenic response to ischemia in diabetic mice and was associated with increased HMGB-1 and VEGF levels in muscle tissues.
Highlights
Diabetic patients with peripheral artery disease are known to be at a higher risk of developing critical limb ischemia and undergoing limb amputation than nondiabetic patients [1]
In vivo animal experiments with hindlimb ischemia model showed that recovery of blood flow in ischemiainduced limb was slower in diabetic animals than nondiabetic animals [2, 3]
Various pathomechanisms have been suggested for the impaired angiogenic response in diabetic patients such as endothelial dysfunction, decreased endothelial nitric oxide synthetase activity, attenuated function of endothelial progenitor cells and bone marrow cells [4], chronic inflammation due to increased reactive oxygen species and advanced glycation end products (AGE), resistance to vascular endothelial growth factor (VEGF), and reduced growth factor levels in the ischemic limb [5, 6]
Summary
Diabetic patients with peripheral artery disease are known to be at a higher risk of developing critical limb ischemia and undergoing limb amputation than nondiabetic patients [1]. Various pathomechanisms have been suggested for the impaired angiogenic response in diabetic patients such as endothelial dysfunction, decreased endothelial nitric oxide synthetase activity, attenuated function of endothelial progenitor cells and bone marrow cells [4], chronic inflammation due to increased reactive oxygen species and advanced glycation end products (AGE), resistance to vascular endothelial growth factor (VEGF), and reduced growth factor levels in the ischemic limb [5, 6]. The treatment with sRAGE significantly increased the VEGF and HMGB-1 protein expression in the ischemic limb muscle tissues in the diabetic mice. The suppression of RAGE by sRAGE administration improved angiogenic response to ischemia in diabetic mice and was associated with increased HMGB-1 and VEGF levels in muscle tissues
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