Systemic Administration of Ribbon-type Decoy Oligodeoxynucleotide Against Nuclear Factor κB and Ets Prevents Abdominal Aortic Aneurysm in Rat Model
Systemic Administration of Ribbon-type Decoy Oligodeoxynucleotide Against Nuclear Factor κB and Ets Prevents Abdominal Aortic Aneurysm in Rat Model
复制标题
DOI：
10.1038/mt.2010.208
复制
发表时间：
2011-01-01
影响因子：
12.4
通讯作者：
Morishita, Ryuichi
中科院分区：
文献类型：
--
作者：
Miyake, Takashi;Aoki, Motokuni;Morishita, Ryuichi
目前，临床上尚无有效的治疗方法来预防腹主动脉瘤（AAA）。为了开发一种新的治疗方法，我们将针对核因子 kappa B (NF kappa B) 和 et 的诱饵寡脱氧核苷酸 (ODN) 修饰为带状圆形结构，无需化学修饰，以增加其对核酸内切酶的抵抗力，用于全身给药。在弹性蛋白酶诱导的大鼠 AAA 模型中腹膜内施用带状诱饵 ODN (R-ODN)。在迁移到动脉瘤壁的巨噬细胞中可以检测到荧光异硫氰酸 (FITC) 标记的 R-ODN，并且嵌合 R-ODN 同时抑制 NF kappa B 和 ets 活性。嵌合 R-ODN 治疗显着抑制主动脉扩张，而传统的硫代磷酸诱饵 ODN 未能阻止动脉瘤形成。使用嵌合 R-ODN 观察到弹性纤维的显着保留，同时巨噬细胞中几种蛋白酶的分泌减少。嵌合 R-ODN 抑制了动脉瘤壁中基质金属蛋白酶 (MMP)-9 和 MMP-12 的激活，但不抑制 MMP-2，但巨噬细胞的募集并未受到抑制。用嵌合 R-ODN 处理还抑制巨噬细胞分泌组织蛋白酶 B 和 K。总体而言，本研究表明，全身施用嵌合 R-ODN 可预防大鼠模型中动脉瘤的形成。诱饵策略的进一步修改将为人类 AAA 提供一种侵入性较小的分子治疗手段。
Currently, there is no effective clinical treatment to prevent abdominal aortic aneurysm (AAA). To develop a novel therapeutic approach, we modified decoy oligodeoxynucleotide (ODN) against nuclear factor kappa B (NF kappa B) and ets, to a ribbon-shaped circular structure without chemical modification, to increase its resistance to endonuclease for systemic administration. Intraperitoneal administration of ribbon-type decoy ODNs (R-ODNs) was performed in an elastase-induced rat AAA model. Fluorescent isothiocyanate (FITC)-labeled R-ODNs could be detected in macrophages migrating into the aneurysm wall, and NF kappa B and ets activity were simultaneously inhibited by chimeric R-ODN. Treatment with chimeric R-ODN significantly inhibited aortic dilatation, whereas conventional phosphorothioate decoy ODN failed to prevent aneurysm formation. Significant preservation of elastic fibers was observed with chimeric R-ODN, accompanied by a reduction of secretion of several proteases from macrophages. Activation of matrix metalloproteinase (MMP)-9 and MMP-12, but not MMP-2, was suppressed in the aneurysm wall by chimeric R-ODN, whereas recruitment of macrophages was not inhibited. Treatment with chimeric R-ODN also inhibited the secretion of cathepsin B and K from macrophages. Overall, the present study demonstrated that systemic administration of chimeric R-ODNs prevented aneurysm formation in a rat model. Further modification of the decoy strategy would provide a means of less invasive molecular therapy for human AAA.