Alagebrium Chloride, a Novel Advanced Glycation End-Product Cross Linkage Breaker, Inhibits Neointimal Proliferation in a Diabetic Rat Carotid Balloon Injury Model.
10.4070/kcj.2010.40.10.520
- Author:
Jin Bae KIM
1
;
Byeong Wook SONG
;
Sungha PARK
;
Ki Chul HWANG
;
Bong Soo CHA
;
Yangsoo JANG
;
Hyun Chul LEE
;
Moon Hyoung LEE
Author Information
1. Cardiology Division, Yonsei University College of Medicine, Seoul, Korea. shpark0530@yuhs.ac
- Publication Type:Original Article
- Keywords:
Alagebrium;
Advanced glycation end-products;
Neointimal hyperplasia
- MeSH:
Animals;
Atherosclerosis;
Carotid Arteries;
Connective Tissue;
Cyclooxygenase 2;
Extracellular Matrix;
Humans;
Hyperplasia;
Inflammation;
Male;
Muscle, Smooth, Vascular;
Neointima;
Phosphorylation;
Phosphotransferases;
Rats;
Reactive Oxygen Species;
Streptozocin;
Thiazoles
- From:Korean Circulation Journal
2010;40(10):520-526
- CountryRepublic of Korea
- Language:English
-
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 microM 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.
