Korean Circ J.  2013 Sep;43(9):592-599. 10.4070/kcj.2013.43.9.592.

Bortezomib Reduces Neointimal Hyperplasia in a Rat Carotid Artery Injury Model

• Kim KS
• Kim SY
• Choi JH
• Joo SJ
• Kim DW
• Cho MC

• KMID: 2224814
• DOI: http://doi.org/10.4070/kcj.2013.43.9.592

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.

Keyword

Coronary restenosis; Angioplasty; Proteasome; Nuclear factor kappa B

MeSH Terms

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
Boronic Acids
NF-kappa B
Proteasome Endopeptidase Complex
Pyrazines