title: Alagebrium chloride, a novel advanced glycation end-product cross linkage breaker, inhibits neointimal proliferation in a diabetic rat carotid balloon injury model.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  Rat aortic vascular smooth muscle cells (RASMCs) were treated with 1-100 µM 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiology Division, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jin-Bae
authors.initials: JB
authors.lastname: Kim
authors.forename: Byeong-Wook
authors.initials: BW
authors.lastname: Song
authors.forename: Sungha
authors.initials: S
authors.lastname: Park
authors.forename: Ki-Chul
authors.initials: KC
authors.lastname: Hwang
authors.forename: Bong-Soo
authors.initials: BS
authors.lastname: Cha
authors.forename: Yangsoo
authors.initials: Y
authors.lastname: Jang
authors.forename: Hyun-Chul
authors.initials: HC
authors.lastname: Lee
authors.forename: Moon-Hyoung
authors.initials: MH
authors.lastname: Lee