Doxycycline delays aneurysm rupture in a mouse model of Marfan syndrome
Doxycycline delays aneurysm rupture in a mouse model of Marfan syndrome
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DOI：
10.1016/j.jvs.2007.09.016
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发表时间：
2008-01-01
影响因子：
4.3
通讯作者：
Baxter, Timothy
中科院分区：
文献类型：
--
作者：
Xiong, Wanfen;Knispel, Rebecca A.;Baxter, Timothy
目的：胸动脉瘤是马凡氏综合征（MFS）的主要心血管并发症，可导致患者过早死亡。MFS与编码纤维蛋白1 （FBN1）的基因突变有关，纤维蛋白1是弹性纤维的主要成分。基质金属蛋白酶（MMPs）在腹主动脉瘤的发病机制中起重要作用，但其在MFS中的确切作用尚不清楚。强力霉素是一种非特异性MMP抑制剂。本研究旨在探讨多环素是否能减轻基质降解，延长mfs小鼠的存活时间。该研究采用了一种具有良好特征的MFS动物模型，即纤原蛋白-1低表达小鼠（mgR/mgR小鼠），这些小鼠在2至4月龄之间因胸主动脉破裂而自然死亡。突变型和野生型小鼠从出生后第1天（PD）开始在其饮用水中给予剂量为100 mg/kg/天的强力霉素，而对照组小鼠则给予水。将治疗后的小鼠分为两组。一组动物被跟踪至死亡或7个月以确定寿命。第二组小鼠于6周取胸升主动脉进行组织学分析（H&E染色、三色染色）和酶谱法检测MMP-2和MW-9水平。mgR/mgR小鼠胸主动脉中MMP-2和MMP-9水平高于野生型。多西环素处理的mgR/mgR小鼠存活132 +/- 14.6天（n = 16）或显著长于未处理的突变小鼠（79 +/- 6.7天，n = 30） （P < 0.01）。结缔组织染色显示强力霉素处理降低了mgR/mgR小鼠弹性纤维的降解。此外，与未处理的mgR/mgR小鼠相比，强力霉素处理的mgR/mgR小鼠MMP-2和MMP-9水平较低。本研究表明，强力霉素通过抑制组织MMP-2和MMP-9的表达，从而抑制弹性基质的降解，显著延缓mfs样小鼠的动脉瘤破裂。结果表明，MMPs有助于MFS胸动脉瘤的进展，强力霉素有可能显著改变疾病的进程。
Objective: Thoracic aneurysms are the main cardiovascular complication of Marfan syndrome (MFS) resulting in premature death. MFS has been associated with mutations of the gene encoding fibrillin-1 (FBN1), a major constituent of the elastic fibers. Matrix metalloproteinases (MMPs) are important in the pathogenesis of abdominal aortic aneurysms but their precise role in MFS is not clear. Doxycycline is a nonspecific MMP inhibitor. The objective of the study was to determine whether docycycline can attenuate matrix degradation and prolong the survival of mice with MFS.Methods. The study employed a well-characterized animal model of MFS, namely fibrillin-1 under-expressing mice (mgR/mgR mice) that die spontaneously from rupture of the thoracic aorta between 2 to 4 months of age. Mutant and wild type mice were given doxycycline in their drinking water at a concentration designed to provide 100 mg/kg/day beginning at postnatal day (PD) 1, whereas control mice were given water. Treated mice were divided into two groups. One group of animals was followed until death or for 7 months to determine lifespan. In the second group of mice, the ascending thoracic aortas were collected for histological analysis (H&E staining, trichrome staining) and zymography for examining MMP-2 and MW-9 levels at 6 weeks.Results. MMP-2 and MMP-9 levels were higher in the thoracic aorta of mgR/mgR mice compared with wild type littermates. Doxycycline- treated mgR/mgR mice lived 132 +/- 14.6 days (n = 16) or significantly longer than untreated mutant mice (79 +/- 6.7 days, n = 30) (P < 0.01). Connective tissue staining showed that doxycycline treatment decreased elastic fiber degradation in mgR/mgR mice. Furthermore, mgR/mgR mice treated with doxycycline had lower MMP-2 and MMP-9 levels compared with untreated mgR/mgR mice.Conclusions. This study demonstrates that doxycycline significantly delays aneurysm rupture in MFS-like mice by inhibiting expression of tissue MMP-2 and MMP-9 and thus, degradation of the elastic matrix. The results suggest that MMPs contribute to the progression of thoracic aneurysm in MFS and that doxycycline has the potential to significantly alter the course of the disease.