Arif Rawa, Zaradzki Marcin, Remes Anca, Seppelt Philipp, Kunze Reiner, Schröder Hannes, Schwill Simon, Ensminger Stephan M, Robinson Peter N, Karck Matthias, Müller Oliver J, Hecker Markus, Wagner Andreas H, Kallenbach Klaus
Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany.
Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany.
Mol Ther Nucleic Acids. 2017 Dec 15;9:69-79. doi: 10.1016/j.omtn.2017.08.014. Epub 2017 Sep 20.
Marfan syndrome is characterized by high expression of matrix metalloproteinases (MMPs) in aortic smooth muscle cells (AoSMCs) associated with medial elastolysis and aortic root aneurysm. We aimed to reduce aortic elastolysis through decrease of MMP expression with decoy oligodeoxynucleotides (dODNs) neutralizing the transcription factor activating factor-1 (AP-1). AP-1 abundance in nuclear extracts as well as MMP-2 and MMP-9 expression were significantly increased in isolated mAoSMC of mgR/mgR Marfan mice compared to wild-type cells. Exposure to AP-1 neutralizing dODNs resulted in a significant reduction of basal and interleukin-1β-stimulated MMP expression and activity in mAoSMCs. Moreover, increased migration and formation of superoxide radical anions was substantially decreased in mAoSMCs by AP-1 dODN treatment. Aortic grafts from donor Marfan mice were treated with AP-1- dODN ex vivo and implanted as infrarenal aortic interposition grafts in mgR/mgR mice. Pretreatment of aortic grafts with AP-1 dODN led to reduced elastolysis, macrophage infiltration, and MMP activity. Permeability of the endothelial monolayer was increased for dODN in mgR/mgR aortae with observed loss of tight junction proteins ZO-1 and occludin, enabling dODN to reach the tunica media. Targeting AP-1 activity offers a new potential strategy to treat the vascular phenotype associated with Marfan syndrome.
马凡综合征的特征是主动脉平滑肌细胞（AoSMCs）中基质金属蛋白酶（MMPs）高表达，这与中层弹力纤维溶解和主动脉根部瘤形成有关。我们旨在通过使用诱饵寡脱氧核苷酸（dODNs）中和转录因子激活因子-1（AP-1）来降低MMP表达，从而减少主动脉弹力纤维溶解。与野生型细胞相比，mgR/mgR马凡小鼠分离的主动脉平滑肌细胞（mAoSMC）中核提取物中的AP-1丰度以及MMP-2和MMP-9表达显著增加。暴露于AP-1中和dODNs导致mAoSMCs中基础和白细胞介素-1β刺激的MMP表达及活性显著降低。此外，AP-1 dODN处理使mAoSMCs中增加的迁移和超氧阴离子自由基形成大幅减少。来自供体马凡小鼠的主动脉移植物在体外接受AP-1-dODN处理，并作为肾下腹主动脉间置移植物植入mgR/mgR小鼠体内。用AP-1 dODN预处理主动脉移植物可减少弹力纤维溶解、巨噬细胞浸润和MMP活性。在mgR/mgR主动脉中，dODN可增加内皮单层的通透性，观察到紧密连接蛋白ZO-1和闭合蛋白丢失，使dODN能够到达中膜。靶向AP-1活性为治疗与马凡综合征相关的血管表型提供了一种新的潜在策略。
