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Author Notes:

Correspondence: Dr WR Taylor, MD, PhD, Division of Cardiology, Emory University, 101 Woodruff Circle, Suite 319 WMB, Atlanta, GA 30322, USA. E-mail: w.robert.taylor@emory.edu

Disclosure/Duality of Interest: none

Subjects:

Research Funding:

This work was supported in part by NIH P01HL095070 (WRT), T32 HL007745 (DG) and NIH F32HL124974 (LH)

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, Research & Experimental
  • Pathology
  • Research & Experimental Medicine
  • CHROMATIN PROTEIN HMGB1
  • GROUP BOX-1 PROTEIN
  • FACTOR-KAPPA-B
  • ANGIOGENIC RESPONSE
  • ENDOTHELIAL-CELLS
  • MAILLARD REACTION
  • OXIDANT STRESS
  • RAGE
  • N-EPSILON-(CARBOXYMETHYL)LYSINE
  • ACTIVATION

The receptor for advanced glycation end products impairs collateral formation in both diabetic and non-diabetic mice

Tools:

Journal Title:

Laboratory Investigation

Volume:

Volume 97, Number 1

Publisher:

, Pages 34-42

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Diabetics often have poor perfusion in their limbs as a result of peripheral artery disease and an impaired ability to generate collateral vessels. The receptor for advanced glycation end products (RAGE) is one protein that is thought to play a detrimental role in collateral development in diabetics due to increased levels of advanced glycation end products (AGE), one of its ligands, in diabetes. Thus, the aim of this study was to investigate the role of RAGE in both diabetic and non-diabetic settings in a model of collateral formation in mice. Streptozotocin was used to induce diabetes in both wild type and RAGE knockout mice. Increased levels of the AGE, N ϵ -(carboxymethyl) lysine (CML), were confirmed via an ELISA. A hindlimb ischemia model, in which the femoral artery is ligated, was used to drive collateral growth and reperfusion was assessed using laser Doppler perfusion imaging and histological analysis of vessels in the muscle. Both of these measurements showed impaired collateral growth in diabetic compared with wild-type mice as well as improved collateral growth in both diabetic and non-diabetic RAGE knockout mice when compared their wild-type counterparts. Distance on a freely accessed running wheel, used as a measure of perfusion recovery, showed that wild-type diabetic mice had functionally impaired recovery compared with their wild-type counterparts. Immunohistochemistry and immunoblotting showed that HMGB-1 (high-mobility group box 1), another RAGE ligand, was increased in the ischemic leg compared with the non-ischemic leg in all mice. This increase in HMGB-1 may explain improvement in animals lacking RAGE and its subsequent signaling. In conclusion, this study shows that RAGE impairs collateral growth in a diabetic setting and also in a non-diabetic setting. This demonstrates the importance of RAGE and alternate RAGE ligands in the setting of collateral vessel growth.

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This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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