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ȣ - 490490 204 |
| Sulfasalazine reduces neointimal hyperplasia in rat carotid artery balloon injury model by inhibition of NF-κB signaling and activation of Nrf-2. |
| 서울대학교 의과대학 내과학 교실¹ , 서울대학교 병원 임상의학연구소 심혈관 연구실², 분당서울대학교병원 순환기 내과 ³ |
| 서정주¹, 김주영² , 김태연² , 강현재¹ , 최동주³ , 김효수¹ , 김철호³ , 오병희¹ , 박영배¹ , 최윤식 ¹ |
BACKGROUND: Sulfasalazine(SSZ) has been used as anti-inflammatory and immunomodulatory drug in the treatment of inflammatory bowel disease and rheumatoid arthritis. The transcription factor NF-κB is known to play a pivotal role in the activation of inflammatory genes, thus inducing proliferative vascular disorders. In recent years, the transcription factor NF-E2 related factor(Nrf2) has been reported to regulate the expression of antioxidant and detoxification genes such as heme oxygenase-1(HO-1). We hypothesized that SSZ might reduce neointimal hyperplasia in rat carotid artery balloon injury model. METHODS: Rat vascular smooth muscle cells were cultured in the presence of SSZ(100 μM). Cell cycle changes and degree of apoptosis was evaluated by FACS analyses. NF-κB activation was evaluated by electrophoretic mobility shift assay and expression of HO-1 and Nrf2 was evaluated by Western blot. For in vivo experiments, rat carotid artery balloon injury model was used to test the effects of SSZ and vehicle on neointimal growth. Rats were divided into 2 groups(n=5/group): SSZ(86 mg/kg/d) and vehicle(normal saline). Drugs were administered via intraperitoneal injection from 3 days before to 2 weeks after balloon injury. RESULTS: 1) In vitro, SSZ significantly increased TNF-α–mediated apoptosis and induced cell cycle arrest in rat vascular smooth muscle cells(VSMCs). Apoptosis induction by SSZ was reversed by antioxidant, NAC, suggesting effect of SSZ was mediated by oxidative stress. SSZ significantly inhibited TNF-α-mediated activation of NF-κB and increased HO-1 expression via activation of Nrf2. 2) In vivo, SSZ reduced neointimal hyperplasia after balloon-injury in rat carotid artery(p<0.05). Tissue immunoblot showed significant increase of caspase-3 in SSZ-treated carotid artery, suggesting reduced hyperplasia resulted from increased apoptosis of VSMCs. CONCLUSIONS: SSZ was found to have a potent inhibiting effect of neointimal hyperplasia via inhibition of NF-κB signaling. This study suggests that those inhibiting effect of SSZ was mediated by antioxidant mechanism via activation of Nrf-2 and induction of HO-1 and that SSZ might be a potential agent in preventing restenosis after angioplasty.
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