Abstract 324: RAGE Deficiency Contributes to Increased Induction of Angiogenesis in Hindlimb Ischemia in Diabetic Mice by Modulation of Hypoxia- and Inflammatory Dependent Gene Expression
People with diabetes are at higher risk of developing ischemic vascular disease, including peripheral artery disease (PAD). Prior studies highlighted the importance of midkine for induction of angiogenesis associated with vascular repair process in the hindlimb ischemia model and suggested that the hypoxia inducible factor (HIF) pathway may be involved in midkine expression in human polymorphonuclear neutrophils (PMN), monocytes and endothelial cells under hypoxia. Our previous data showed that genetic deletion of receptor for advanced glycation endproducts (RAGE) improved restoration of angiogenesis and blood flow in hindlimb ischemia in diabetic mice. Here, we tested the hypothesis that RAGE deficiency would upregulate expression of certain genes responsible for the coordination of inflammatory response and angiogenesis in hindlimb 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 on day 7 after surgery. Using “Angiogenesis” focused PCR array, gene expression profiling identifies upregulation of inflammation and angiogenesis-related genes impacted by diabetes and RAGE in hindlimb ischemia. In addition to our earlier findings of striking increase in monocyte chemotactic protein-1 (Mcp-1/Ccl2) and CD68+ cells in D RAGE-/- mice vs D WT mice, there were ≈ 6.5-, 4-, 3.8-, 4.8-, 4.7- and 4.3-fold increases in midkine (Mdk), Hif-1α, interleukin (IL)-1β, Itgβ3, chemokine (C-X-C motif) ligand 2 (Cxcl2) and matrix metalloproteinases (Mmp)19 transcripts in response to ischemia in D RAGE-/- vs. D WT mice. These data link RAGE deficiency to increased expression of the above inflammatory and/or angiogenic genes in ischemia, especially in diabetes. This may provide a basis for further elucidating the molecular mechanisms by which RAGE modulates hypoxia and inflammation-modulating gene expression for induction of angiogenesis in the setting of limb ischemia in diabetes, and may have the potential to provide a novel therapeutic target for diabetic complications.
Author Disclosures: Y. Xu: None. X. Shen: None. R. Rosario: None. A. Schmidt: None. S. Yan: None.
- © 2014 by American Heart Association, Inc.