Korean Circulation Journal

The Korean Society of Cardiology (대한심장학회)
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Bortezomib Reduces Neointimal Hyperplasia in a Rat Carotid Artery Injury Model

  • Kim, Ki-Seok (Department of Medicine, College of Medicine, Jeju National University) ;
  • Kim, Song Yi (Department of Medicine, College of Medicine, Jeju National University) ;
  • Choi, Joon Hyeok (Department of Medicine, College of Medicine, Jeju National University) ;
  • Joo, Seung Jae (Department of Medicine, College of Medicine, Jeju National University) ;
  • Kim, Dong Woon (Department of Medicine, College of Medicine, Chungbuk National University) ;
  • Cho, Myeong Chan (Department of Medicine, College of Medicine, Chungbuk National University)
  • Published : 2013.09.30
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Abstract

Background and Objectives: The ubiquitin-proteasome system is the major intracellular protein degradation pathway in the eukaryotic cells. Bortezomib inhibits 26S proteasome-induced $I-{\kappa}B{\alpha}$ degradation and suppresses nuclear factor-kappa B ($NF-{\kappa}B$) 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 $NF-{\kappa}B$ and $I-{\kappa}B{\alpha}$. 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-$I-{\kappa}B{\alpha}$ expression, which suggested the inhibition of $I-{\kappa}B{\alpha}$ degradation. On immunofluorescence analysis, the nuclear import of $NF-{\kappa}B$ was clearly decreased in the systemic bortezomib group. The perivascular bortezomib treatment group exhibited a significant reduction in the neointimal area ($0.21{\pm}0.06mm^2$ vs. $0.06{\pm}0.01mm^2$, p<0.05), the neointima/ media area ratio ($1.43{\pm}0.72$ vs. $0.47{\pm}0.16$, p<0.05) and the % area stenosis ($45.5{\pm}0.72%$ vs. $14.5{\pm}0.05%$, p<0.05) compared with the control group. In situ vascular smooth muscle cell proliferation at 2 days after the injury was significantly inhibited ($24.7{\pm}10.9%$ vs. $10.7{\pm}4.7%$, p<0.05). Conclusion: Bortezomib suppressed $NF-{\kappa}B$ activation through the inhibition of $I-{\kappa}B{\alpha}$ 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.

Keywords

References

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