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首页> 外文期刊>American Journal of Physiology >Attenuation of neointima formation through the inhibition of DNA repair enzyme PARP-1 in balloon-injured rat carotid artery.
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Attenuation of neointima formation through the inhibition of DNA repair enzyme PARP-1 in balloon-injured rat carotid artery.

机译：通过抑制DNA修复酶PARP-1抑制球囊损伤大鼠颈动脉中新内膜的形成。

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Increased oxidative stress is a major characteristic of restenosis after angioplasty. The oxidative stress is mainly created by oxidants such as reactive oxygen species (ROS), which are assumed to play an important role in neointima formation after angioplasty. DNA is a sensitive target for oxidants; however, oxidative DNA damage remains a poorly examined field in the pathogenesis of restenosis. In the present study, we demonstrated that the expression of the oxidative DNA damage marker 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) was quickly increased in rat carotid arteries after balloon injury. It reached its peak at 14 days after injury and still kept high expression at 28 days after injury. The immunostaining of 8-oxo-dG was present predominantly in the neointima. In response to oxidative DNA damage, the DNA repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1) was significantly increased after balloon injury. The time course change and location of PARP-1 is similar to that of 8-oxo-dG. Daily injections of the PARP-1 inhibitor PJ34 (5 mg.kg(-1).day(-1) ip) attenuated neointima formation by approximately 40% at 7, 14, and 28 days after balloon injury. Treatment with PJ34 inhibited leukocyte infiltration and improved both anatomic (reendothelialization) and functional (endothelial function) recovery of endothelial cells after balloon injury. In conclusion, levels of oxidative DNA damage and the DNA repair enzyme PARP-1 are increased in vessels after balloon injury. Inhibition of PARP-1 attenuates neointima formation through inhibition of leukocyte infiltration and improvement of endothelial cell recovery after balloon injury. Targeting of the DNA repair enzyme might be a therapeutic strategy for restenosis.
机译：氧化应激增加是血管成形术后再狭窄的主要特征。氧化应激主要由氧化剂引起，例如活性氧（ROS），它们被认为在血管成形术后新内膜形成中起重要作用。 DNA是氧化剂的敏感靶标。然而，氧化性DNA损伤在再狭窄的发病机制中仍然是一个研究不足的领域。在本研究中，我们证明了在气球损伤后大鼠颈动脉中，氧化性DNA损伤标记7,8-dihydro-8-oxo-2'-deoxyguanosine（8-oxo-dG）的表达迅速增加。它在受伤后第14天达到峰值，在受伤后第28天仍保持高表达。 8-氧代-dG的免疫染色主要存在于新内膜中。响应于氧化性DNA损伤，气球修复后，DNA修复酶聚（ADP-核糖）聚合酶-1（PARP-1）显着增加。 PARP-1的时程变化和位置与8-oxo-dG相似。每天注射PARP-1抑制剂PJ34（5 mg.kg（-1）.day（-1）ip）在球囊损伤后第7、14和28天可使新内膜形成减少约40％。 PJ34的治疗抑制了白细胞浸润，并改善了球囊损伤后内皮细胞的解剖学（再内皮化）和功能性（内皮功能）恢复。总之，球囊损伤后血管中的氧化性DNA损伤水平和DNA修复酶PARP-1升高。 PARP-1的抑制作用通过抑制白细胞浸润和改善球囊损伤后内皮细胞的恢复来减弱新内膜的形成。 DNA修复酶的靶向可能是再狭窄的治疗策略。

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