Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in Marfan syndrome through the inhibition of matrix metalloproteinase-2 and-9
Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in Marfan syndrome through the inhibition of matrix metalloproteinase-2 and-9
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DOI：
10.1161/circresaha.108.174367
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发表时间：
2008-04-25
影响因子：
20.1
通讯作者：
van Breemen, Cornelis
中科院分区：
文献类型：
--
作者：
Chung, Ada W. Y.;Yang, H. H. Clarice;van Breemen, Cornelis
β受体阻滞剂（例如阿替洛尔）是马凡氏综合征患者胸主动脉瘤（TAA）的基础治疗方法;然而，有报道称主动脉持续扩张。我们已经证明，基质金属蛋白酶（MMP）-2和-9在马凡综合征TAA的进展过程中上调，伴随着弹性纤维变性和血管功能障碍。我们假设，强力霉素，一种非特异性的MMPs抑制剂，将减轻TAA的弹性纤维变性和改善血管功能。使用马凡氏综合征的良好表征的小鼠模型（Fbn 1（C1039 G/+））。在6周龄时，小鼠未经处理（n = 40），给予强力霉素（0.24g/L，n = 30）或给予阿替洛尔（0.5g/L，n = 30）饮水。Fbn 1（+/+）小鼠作为对照（n = 40）。在3、6和9个月时，使用升、弓和降部分的主动脉节段获得整个胸主动脉的“平均”值。多西环素组的TAA得以预防，而阿替洛尔组的轻度动脉瘤明显。强力霉素改善弹性纤维完整性，使主动脉僵硬度正常化，并防止血管弱化。多西环素可改善阿替洛尔组和未治疗组的血管收缩和内皮依赖性舒张功能障碍。马凡氏主动脉中转化生长因子-β的上调被强力霉素抑制。强力霉素增加MMP的组织抑制剂与MMP的表达比率。腹腔注射抗MMP-2和-9的中和抗体产生了与强力霉素相似的效果。我们的结论是，通过抑制MMP-2和MMP- 9，长期使用强力霉素治疗比阿替洛尔更有效地预防马凡氏综合征TAA，保持弹性纤维的完整性，正常化血管功能，减少转化生长因子-β激活。
beta-Blockers, eg, atenolol, are the cornerstone therapy for thoracic aortic aneurysm ( TAA) in patients with Marfan syndrome; however, continued aortic dilatation has been reported. We have demonstrated that matrix metalloproteinase ( MMP)-2 and - 9 were upregulated during progression of TAA in Marfan syndrome, accompanied with degenerated elastic fibers and vasomotor dysfunction. We hypothesized that doxycycline, a nonspecific inhibitor of MMPs, would ameliorate TAA by attenuating elastic fiber degeneration and improving vasomotor function. A well-characterized mouse model of Marfan syndrome ( Fbn1(C1039G/+)) was used. Mice were untreated ( n = 40), given doxycycline ( 0.24g/L, n = 30), or given atenolol ( 0.5g/L, n = 30) in drinking water at 6 weeks of age. The Fbn1(+/+) mice served as control ( n = 40). At 3, 6, and 9 months, aortic segments from the ascending, arch, and descending portions were used to obtain the "average" value of the whole thoracic aorta. TAA was prevented in the doxycycline group, whereas mild aneurysm was evident in the atenolol group. Doxycycline improved elastic fiber integrity, normalized aortic stiffness, and prevented vessel weakening. The impairment of vasocontraction and endothelium-dependent relaxation in the untreated and atenolol groups were improved by doxycycline. The upregulation of transforming growth factor-beta in the Marfan aorta was suppressed by doxycycline. Doxycycline augmented expression ratios of tissue inhibitors of MMP to MMPs. Intraperitoneally injected neutralizing antibodies against MMP-2 and - 9 yielded similar effects to doxycycline. We concluded that long-term treatment with doxycycline, through the inhibition of MMP-2 and - 9, is more effective than atenolol in preventing TAA in Marfan syndrome by preserving elastic fiber integrity, normalizing vasomotor function, and reducing transforming growth factor-beta activation.