MMP-2 regulates Erk1/2 phosphorylation and aortic dilatation in Marfan syndrome.
MMP-2 regulates Erk1/2 phosphorylation and aortic dilatation in Marfan syndrome.
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DOI：
10.1161/circresaha.112.268268
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发表时间：
2012-06-08
影响因子：
20.1
通讯作者：
Baxter BT
中科院分区：
文献类型：
--
作者：
Xiong W;Meisinger T;Knispel R;Worth JM;Baxter BT
胸升主动脉瘤和夹层是马凡氏综合征（MFS）的主要心血管并发症，可导致过早死亡。使用MFS小鼠模型的研究表明，转化生长因子（TGF）-β的活化和伴随的基质金属蛋白酶（MMPs）的上调有助于动脉瘤的发展。我们以前的研究表明，在MFS小鼠模型中，多西环素延迟动脉瘤破裂，Fbn 1 mgR/mgR。在另一种MFS小鼠模型Fbn 1 C1039 G/+中，氯沙坦已被证明可通过抑制Erk 1/2通路预防动脉瘤。然而，MMP-2在MFS中的作用以及氯沙坦对MFS小鼠寿命的影响尚不清楚。我们研究了MMP-2在MFS中的作用，并比较了氯沙坦和多西环素对Fbn 1 mgR/mgR小鼠主动脉扩张和存活的影响。通过生命表分析，我们发现氯沙坦和多西环素能提高Fbn 1 mgR/mgR小鼠的存活率。明胶酶谱和蛋白质印迹数据显示，只有强力霉素抑制MMP-2的表达，而这两种药物降低Erk 1/2磷酸化。当合并时，9只小鼠中只有1只在30周研究内死亡;主动脉组织学和直径正常化，对Smad 2磷酸化的影响是累加的。为了进一步探讨MMP-2在MFS中的作用，我们建立了MMP-2缺陷型Fbn 1 mgR/mgR小鼠。MMP-2缺失可抑制TGF-β的活化和Erk 1/2、Smad 2的磷酸化，延长小鼠寿命。这些研究表明，多西环素抑制MMP-2可延迟MFS的表现，部分原因是其能够降低活性TGF-β和TGF-β下游的非经典信号级联反应。这项研究进一步表明，在不同点靶向TGF-β信号可能是抑制疾病进展的更有效策略。
Aneurysm and dissection of the ascending thoracic aorta are the main cardiovascular complication of Marfan Syndrome (MFS) resulting in premature death. Studies using mouse models of MFS have shown that activation of transforming growth factor (TGF)-β and the concomitant up-regulation of matrix metalloproteinases (MMPs) contribute to aneurysm development. Our previous study showed that doxycycline delayed aneurysm rupture in a mouse model of MFS, Fbn1mgR/mgR. Losartan has been shown to prevent aneurysms in another mouse model of MFS, Fbn1 C1039G/+, through inhibition of the Erk1/2 pathway. However, the role of MMP-2 in MFS and effect of losartan on the lifespan of MFS mice remain unknown. We investigated the role of MMP-2 in MFS and compared the effects of losartan and doxycycline on aortic dilatation and survival in Fbn1mgR/mgR mice. By life table analysis, we found that losartan and doxycycline improved the survival of Fbn1mgR/mgR mice. Gelatin zymography and Western blot data showed that only doxycycline inhibited MMP-2 expression while both drugs decreased Erk1/2 phosphorylation. When combined, only one of 9 mice died within the 30 week study; aortic histology and diameter were normalized and the effects on Smad2 phosphorylation was additive. To further explore the role of MMP-2 in MFS, we created MMP-2-deficient Fbn1mgR/mgR mice. MMP-2 deletion inhibited activation of TGF-β and phosphorylation of Erk1/2 and Smad2 and prolonged the lifespan of the mice. These studies demonstrated that inhibition of MMP-2 by doxycycline delayed the manifestations of MFS, in part, through its ability to decrease active TGF-β and the noncanonical signaling cascade downstream of TGF-β. This study further suggested that targeting TGF-β signaling at different points might be a more effective strategy for inhibiting disease progression.