Korean Circulation Journal

The Korean Society of Cardiology (대한심장학회)
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Alagebrium Chloride, a Novel Advanced Glycation End-Product Cross Linkage Breaker, Inhibits Neointimal Proliferation in a Diabetic Rat Carotid Balloon Injury Model

  • Kim, Jin-Bae (Cardiology Division, Yonsei Cardiovascular Center and Cardiovascular Research Institute, Yonsei University College of Medicine) ;
  • Song, Byeong-Wook (Yonsei Cardiovascular Center and Cardiovascular Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine) ;
  • Park, Sung-Ha (Cardiology Division, Yonsei Cardiovascular Center and Cardiovascular Research Institute, Yonsei University College of Medicine) ;
  • Hwang, Ki-Chul (Cardiology Division, Yonsei Cardiovascular Center and Cardiovascular Research Institute, Yonsei University College of Medicine) ;
  • Cha, Bong-Soo (Division of Endocrinology, Yonsei University College of Medicine) ;
  • Jang, Yang-Soo (Cardiology Division, Yonsei Cardiovascular Center and Cardiovascular Research Institute, Yonsei University College of Medicine) ;
  • Lee, Hyun-Chul (Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine) ;
  • Lee, Moon-Hyoung (Cardiology Division, Yonsei Cardiovascular Center and Cardiovascular Research Institute, Yonsei University College of Medicine)
  • Received : 2008.10.27
  • Accepted : 2010.04.29
  • Published : 2010.10.30
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Abstract

Background and Objectives: Vascular perturbation induced by advanced glycation end-products (AGEs) leads to progression of atherosclerosis, plaque instability, and vascular inflammation, which results in a higher risk of neointimal proliferation. Here we investigated the inhibitory effect of alagebrium chloride (ALT-711), a breaker of AGE-based cross links, on neointimal proliferation in a carotid artery balloon injury model in diabetic rats induced by streptozotocin (STZ). Materials and Methods: Rat aortic vascular smooth muscle cells (RASMCs) were treated with 1-100 ${\mu}$M of alagebrium added 24 hours before the addition of AGEs. This in vivo study was done using 8-week-old male rats that were injected intraperitoneally with 80 mg/kg STZ. Sixteen weeks later, the diabetic rats were treated with 10 mg/kg alagebrium for 4 weeks, after which carotid artery balloon injury was induced. After 4 weeks, the animals were sacrificed for histological analysis. Results: Proliferation of RASMCs was significantly inhibited in alagebrium-treated cells. Alagebrium dose-dependently inhibited AGE-mediated formation of reactive oxygen species (ROS), extracellular signal-regulated kinase phosphorylation, and cyclooxygenase-2 expression. The cellular mechanisms of AGE-induced connective tissue and extracellular matrix expression were decreased in the alagebrium-treated group. This in vivo study shows that expression of AGE receptors and neointima hyperplasia are significantly suppressed in balloon-injured rats treated with alagebrium. Conclusion: Alagebrium treatment in diabetic rats significantly inhibits neointimal hyperplasia after carotid balloon injury due to its inhibition of intracellular ROS synthesis, which results in inhibition of RASMCs proliferation.

Keywords

References

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