Modifiable Effects of Rapamycin on Vascular Remodeling via Repair of Oxidative DNA Damage

为了评估雷帕霉素（西罗莫司）通过修复氧化DNA损伤对血管重塑的修饰作用，我们研究了应用雷帕霉素的药物洗脱支架（DES）对经皮冠状动脉介入治疗中新生内膜形成的抑制作用。DES的植入增加了中性粒细胞中活性氧的产生，抑制了炎症过程。DES的这些保护作用通过血管紧张素受体阻断而增强。我们从分离的人白细胞中提取RNA并纯化AP核酸内切酶（Ape 1/ref 1）的DNA，AP核酸内切酶是氧化损伤DNA的主要碱基切除修复（BER）酶。用特异性质粒和腺病毒将pcDNA/Ape 1和pcDNA/LacZ转染损伤血管。在血管丝损伤部位，Ape 1基因的表达较未损伤的正常血管明显增强，提示Ape 1在血管重塑过程中起重要作用。这些结果表明，通过调节BER系统的抗氧化修复机制可能提供了一种新的抗动脉粥样硬化作用。通过修饰氧化DNA-BER系统调节血管重构是抗动脉粥样硬化治疗的一个很有前途的新靶点。

For the assessment of modifiable effects of Rapamycin (sirolimus) on vascular remodeling via repair of oxidative DNA damage, we studied the effects of drug-eluting stent (DES) applied rapamicin on the suppression of neointimal formation in percutaneous coronary intervention. Implantation of DES enhanced production of reactive oxygen species (ROS) in neutrophils and suppressed inflammatory process. These protective actions of DES were enhanced by an angiotensin receptor blockade. We extracted RNA from isolated human leukocytes and purified DNA of AP endonuclease (Ape1/ref1), which is a major base excision repair (BER) enzyme for oxidative-damaged DNA. Using a specific plasmid and adenovirus, pcDNA/Ape1 and pcDNA/LacZ were transfected to injured vessels. At the site of wire-injured vessels, the expression of Ape1 gene was significantly enhanced compared to non-injured normal vessels, suggesting an important role of Ape1 in the process of vascular remodeling. These results suggested that antioxidative repair mechanism through the regulation of BER system may provide a novel antiatherosclerotic action. Regulation of vascular remodeling through the modification of oxidative DNA-BER system is a promising novel target of antiatherosclerotic therapy.