Abstract 17022: RAGE Suppresses Adaptive Upregulation of MCP-1 in Hind Limb Ischemia in Diabetic Mice
Diabetic subjects with foot ulceration and critical limb ischemia are at high risk for lower-extremity amputations. Our previous findings revealed that receptor for advanced glycation endproducts (RAGE) impaired angiogenesis and blood flow recovery in hind limb ischemia in diabetic mice. Here, we tested the hypothesis that RAGE modulates gene expression changes in the inflammatory response to hind limb ischemia in diabetic mice. Wild type (WT) and RAGE-/- mice were rendered diabetic (D) with streptozotocin (stz); non-diabetic (ND) cohorts were treated with buffer alone. After two months of diabetes, at age 16 weeks, mice were subjected to femoral artery (FA) ligation. RNA was prepared from muscle tissues distal to the ligation on day 7 after surgery and subjected to gene expression profiling using “Angiogenesis” focused PCR arrays to identify the genes impacted by diabetes and RAGE in hind limb ischemia. An ≈ 8-fold increase in monocyte chemotactic protein-1 (MCP-1/CCL2) was observed in D RAGE-/- mice vs D WT mice post-ligation. These results were further validated by real-time PCR analysis. Our data demonstrated significant increase in MCP-1/CCL2 transcripts in RAGE/- vs. WT mice in non-diabetes post-ligation as well (p<0.05). In parallel, on day 7 post-ligation, significantly increased CD68+ cells were evident in RAGE-/- vs. WT mice muscle tissues in both non-diabetes and diabetes (p<0.05). Quite the opposite was observed in atherosclerosis and acute hypoxia in mouse hearts in which RAGE deletion sharply reduced MCP-1 transcripts. These data link RAGE deficiency to increased inflammation and macrophage infiltration in ischemic muscles, especially in diabetes, associated with angiogenesis in vascular repair process and suggest unique setting-specific RAGE-dependent regulation of macrophage migration. Taken together, these data provide novel preventive and therapeutic targets for diabetic complications in the peripheral vascular system.
- © 2012 by American Heart Association, Inc.