Vascular injury involves the overoxidation of peroxiredoxin type II and is recovered by the peroxiredoxin activity mimetic that induces reendothelialization.
Vascular injury involves the overoxidation of peroxiredoxin type II and is recovered by the peroxiredoxin activity mimetic that induces reendothelialization.
复制标题
DOI：
10.1161/circulationaha.113.001725
复制
发表时间：
2013-08-20
期刊：
影响因子：
37.8
通讯作者：
Kang SW
中科院分区：
文献类型：
--
作者：
Kang DH;Lee DJ;Kim J;Lee JY;Kim HW;Kwon K;Taylor WR;Jo H;Kang SW
典型的 2-Cys 过氧化还原蛋白 (Prx) 在氧化应激下因过氧化半胱氨酸残基的过度氧化而失活。然而，其在血管疾病中的意义尚不清楚。免疫组织化学分析表明，2-Cys Prxs，特别是 II 型 Prx，在球囊损伤的啮齿动物颈动脉和人类动脉粥样硬化病变中严重过度氧化。与这一观察结果一致，Prx II 的选择性消耗加剧了受损颈动脉中的新内膜增生。我们还发现表聚硫二氧代哌嗪类真菌代谢物表现出模仿 2-Cys Prx 过氧化物酶的酶样活性，并明显消除血管细胞中的细胞内 H2O2。从功能上讲，表聚硫二氧代哌嗪通过取代 Prx II 相互调节这些血管细胞中血小板衍生生长因子受体 - β 和血管内皮生长因子受体介导的信号传导。结果，表聚硫二氧代哌嗪在体外抑制平滑肌细胞的增殖和迁移活性，但促进内皮细胞的增殖和迁移活性。此外，将表聚硫二氧代哌嗪给药于受损的颈动脉，通过抑制新内膜增生而不引起细胞毒性并同时诱导再内皮化而成功恢复。这项研究首次揭示了 2-Cys Prx 过度氧化的参与，以及其活性模拟物在血管损伤（如支架置入术）中的治疗用途。
Typical 2-Cys peroxiredoxin (Prx) is inactivated by overoxidation of the peroxidatic cysteine residue under oxidative stress. However, the significance in the context of vascular disease is unknown. Immunohistochemical analyses revealed that 2-Cys Prxs, particularly Prx type II, are heavily overoxidized in balloon-injured rodent carotid vessels and in human atherosclerotic lesions. Consistent with this observation, the selective depletion of Prx II exacerbated neointimal hyperplasia in injured carotid vessels. We also found that the epipolythiodioxopiperazine class of fungal metabolites exhibited an enzyme-like activity mimicking 2-Cys Prx peroxidase and manifestly eliminated the intracellular H2O2 in the vascular cells. Functionally, the epipolythiodioxopiperazines reciprocally regulated the platelet-derived growth factor receptor-β– and vascular endothelial growth factor receptor–mediated signaling in these vascular cells by replacing Prx II. As a consequence, the epipolythiodioxopiperazines inhibited the proliferative and migratory activities of smooth muscle cells but promoted those of endothelial cells in vitro. Moreover, administration of the epipolythiodioxopiperazines to the injured carotid vessels resulted in a successful recovery by inhibiting neointimal hyperplasia without causing cytotoxicity and simultaneously inducing reendothelialization. This study reveals for the first time the involvement of the 2-Cys Prx overoxidation and thus the therapeutic use of their activity mimetic in vascular injuries like stenting.