Identification of a novel therapeutic target for abdominal aortic aneurysm

腹主动脉瘤(AAA)是一种常见病，在不适宜手术治疗的情况下，可导致主动脉破裂，死亡率高。尽管AAA的非手术治疗一直备受期待，但AAA患者主动脉壁的破坏被认为是一个不可逆转的过程。我们发现c-Jun氨基末端激酶(JNK)在人AAA壁上高度激活。我们还发现，JNK活性对于基质金属蛋白酶-9的表达以及抑制细胞外基质(ECM)的生物合成是必不可少的。因此，我们在体内研究了JNK在AAA发病中的作用。我们通过腹主动脉周围应用CaC12建立了小鼠AAA模型，同时激活了JNK和MMPs，并抑制了赖氨酰氧化酶(LOX)，赖氨酰氧化酶是胶原和弹性蛋白纤维必不可少的生物合成酶。我们的数据表明，除了基质金属蛋白酶的活性外，ECM生物合成的抑制可能参与了AAA的发病机制，因为局部LOX基因传递阻止了AAA的形成。JNK特异性抑制剂SP600125可完全抑制CaCl2诱导的AAA的形成。此外，在AAA建立后，SP600125治疗导致主动脉内径缩小，组织结构正常化。SP600125治疗还导致血管紧张素II诱导的AAA在ApoE基因缺失小鼠建立后显著消退，活体动物的一系列超声研究表明。这些数据表明，JNK通过促进组织降解和抑制组织修复，在AAA发病机制中决定了ECM代谢的异常。因此，抑制JNK可能为AAA提供一种新的治疗选择。

Abdominal aortic aneurysm (AAA) is a common disease that, when surgical treatment is inapplicable, results in rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is eagerly awaited, the destruction of the aortic walls in AAA has been considered an irreversible process. We found that c-Jun N-terminal kinase (JNK) is highly activated in human AAA walls. We also found that JNK activity is essential for the expression of matrix metalloproteinase (MMP)-9 and, concurrently, suppression of the extracellular matrix (ECM) biosynthesis. We therefore investigated the role of JNK in the pathogenesis of AAA in vivo. We created a mouse AAA model by periaortic application of CaC12, which was accompanied by activation of JNK and MMPs, and suppression of lysyl oxidase (LOX), which is an essential biosynthetic enzyme for collagen and elastin fibers. Our data indicate that, in addition to MMP activities, suppression of ECMbiosynthesis may contribute to the AAA pathogenesis because local LOX gene delivery prevented AAA formation. Treatment of mice with SP600125, a specific JNK inhibitor, completely abrogated the formation of CaCl2induced AAA. Furthermore, SP600125 treatment after the establishment of AAAcaused a reduction in the aortic diameters with normalized tissue architecture. SP600125 treatment also caused significant regression of angiotensin II-induced AAA in ApoE-null mice after its establishment, as demonstrated by serial ultrasonographic studies in live animals. These data demonstrate that JNK dictates the abnormal ECM metabolism in AAA pathogenesis by enhancing tissue degradation and suppressing tissue repair. Therefore, inhibition of JNK may provide a novel therapeutic option for AAA.