Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-7690, USA.
Circ Res. 2012 Jun 8;110(12):e92-e101. doi: 10.1161/CIRCRESAHA.112.268268. Epub 2012 May 1.
Aneurysm and dissection of the ascending thoracic aorta are the main cardiovascular complications of Marfan syndrome (MFS) resulting in premature death. Studies using mouse models of MFS have shown that activation of transforming growth factor-beta (TGF-β) and the concomitant upregulation of matrix metalloproteinases (MMPs) contribute to aneurysm development. Our previous study showed that doxycycline delayed aneurysm rupture in a mouse model of MFS, Fbn1(mgR/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 Fbn1(mgR/mgR) mice.
By life table analysis, we found that losartan and doxycycline improved the survival of Fbn1(mgR/mgR) mice. Gelatin zymography and Western blot data showed that only doxycycline inhibited MMP-2 expression, whereas both drugs decreased Erk1/2 phosphorylation. When combined, only one of nine 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 Fbn1(mgR/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.
马凡综合征（MFS）的主要心血管并发症是升主动脉的动脉瘤和夹层，这会导致患者过早死亡。使用 MFS 小鼠模型的研究表明，转化生长因子-β（TGF-β）的激活和细胞外基质金属蛋白酶（MMPs）的上调共同促进了动脉瘤的发展。我们之前的研究表明，强力霉素可延迟 MFS 小鼠模型 Fbn1(mgR/mgR）中的动脉瘤破裂。拉洛昔芬已被证明可通过抑制 Erk1/2 通路来预防另一种 MFS 小鼠模型 Fbn1(C1039G/+）中的动脉瘤。然而，MMP-2 在 MFS 中的作用以及拉洛昔芬对 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，并比较了拉洛昔芬和强力霉素对 Fbn1(mgR/mgR）小鼠主动脉扩张和生存的影响。
通过生命表分析，我们发现拉洛昔芬和强力霉素可提高 Fbn1(mgR/mgR）小鼠的生存率。明胶酶谱和 Western blot 数据表明，只有强力霉素抑制了 MMP-2 的表达，而两种药物均降低了 Erk1/2 的磷酸化。联合用药时，在 30 周的研究中只有 1/9 的小鼠死亡；主动脉组织学和直径正常化，对 Smad2 磷酸化的影响具有叠加作用。为了进一步探讨 MMP-2 在 MFS 中的作用，我们构建了 MMP-2 缺陷型 Fbn1(mgR/mgR）小鼠。MMP-2 缺失抑制了 TGF-β的激活和 Erk1/2 和 Smad2 的磷酸化，并延长了小鼠的寿命。
这些研究表明，强力霉素抑制 MMP-2 的作用可部分延迟 MFS 的表现，这在一定程度上是通过降低活性 TGF-β和 TGF-β下游的非经典信号级联来实现的。本研究进一步表明，针对 TGF-β信号的不同靶点可能是抑制疾病进展的更有效策略。
