Bortezomib Reduces Neointimal Hyperplasia in a Rat Carotid Artery Injury Model.
10.4070/kcj.2013.43.9.592
- Author:
Ki Seok KIM
1
;
Song Yi KIM
;
Joon Hyeok CHOI
;
Seung Jae JOO
;
Dong Woon KIM
;
Myeong Chan CHO
Author Information
1. Department of Medicine, College of Medicine, Jeju National University, Jeju, Korea. kiseok@jejunu.ac.kr
- Publication Type:Original Article
- Keywords:
Coronary restenosis;
Angioplasty;
Proteasome;
Nuclear factor kappa B
- MeSH:
Active Transport, Cell Nucleus;
Angioplasty;
Animals;
Blotting, Western;
Boronic Acids;
Carotid Arteries;
Carotid Artery Injuries;
Cell Proliferation;
Constriction, Pathologic;
Coronary Restenosis;
Eukaryotic Cells;
Fluorescent Antibody Technique;
Hyperplasia;
Muscle, Smooth, Vascular;
Neointima;
NF-kappa B;
Proteasome Endopeptidase Complex;
Proteolysis;
Pyrazines;
Rats;
Veins;
Bortezomib
- From:Korean Circulation Journal
2013;43(9):592-599
- CountryRepublic of Korea
- Language:English
-
Abstract:
BACKGROUND AND OBJECTIVES: The ubiquitin-proteasome system is the major intracellular protein degradation pathway in the eukaryotic cells. Bortezomib inhibits 26S proteasome-induced I-kappaBalpha degradation and suppresses nuclear factor-kappa B (NF-kappaB) activation. We examined the effect of bortezomib on neointima formation after of a rat carotid artery balloon injury. MATERIALS AND METHODS: After carotid artery balloon denudation, bortezomib was immediately administered by tail vein injection (systemic treatment) and by using an F-127 pluronic gel (perivascular treatment). Two weeks after the injury, we compared the degree of neointima formation in the carotid artery and the tissue expression patterns of NF-kappaB and I-kappaBalpha. RESULTS: The systemic treatment group exhibited a 29% reduction in neointima volume at two weeks after the balloon injury. On the western blot analysis, the bortezomib group exhibited an increased I-kappaBalpha expression, which suggested the inhibition of I-kappaBalpha degradation. On immunofluorescence analysis, the nuclear import of NF-kappaB was clearly decreased in the systemic bortezomib group. The perivascular bortezomib treatment group exhibited a significant reduction in the neointimal area (0.21+/-0.06 mm2 vs. 0.06+/-0.01 mm2, p<0.05), the neointima/media area ratio (1.43+/-0.72 vs. 0.47+/-0.16, p<0.05) and the % area stenosis (45.5+/-0.72% vs. 14.5+/-0.05%, p<0.05) compared with the control group. In situ vascular smooth muscle cell proliferation at 2 days after the injury was significantly inhibited (24.7+/-10.9% vs. 10.7+/-4.7%, p<0.05). CONCLUSION: Bortezomib suppressed NF-kappaB activation through the inhibition of I-kappaBalpha degradation, and significantly reduced neointima formation in a rat carotid artery injury model. These data suggested that bortezomib represented a new potent therapeutic agent for the prevention of restenosis.
