Identification of a novel therapeutic target for abdominal aortic aneurysm

腹主动脉瘤（AAA）是一种常见的疾病，当手术治疗不适用时，导致主动脉破裂，死亡率高。尽管AAA的非手术治疗备受期待，但AAA的主动脉壁破坏被认为是一个不可逆的过程。我们发现c-Jun n -末端激酶（JNK）在人AAA壁上高度活化。我们还发现，JNK活性对于基质金属蛋白酶(MMP)-9的表达以及同时抑制细胞外基质（ECM）生物合成至关重要。因此，我们在体内研究了JNK在AAA发病机制中的作用。我们通过在主动脉周围应用CaC12建立了小鼠AAA模型，该模型伴随着JNK和MMPs的激活，以及赖氨酸氧化酶（LOX）的抑制，赖氨酸氧化酶是胶原和弹性蛋白纤维必需的生物合成酶。我们的数据表明，除了MMP活性外，抑制ecm生物合成可能有助于AAA的发病机制，因为局部LOX基因的传递阻止了AAA的形成。用一种特异性JNK抑制剂SP600125处理小鼠，完全消除了cacl2诱导的AAA的形成。此外，在建立AAA后，SP600125处理导致主动脉直径减小，组织结构正常化。SP600125治疗后，apoe缺失小鼠血管紧张素ii诱导的AAA也有明显的消退，这在活体动物超声连续研究中得到证实。这些数据表明，JNK通过增强组织降解和抑制组织修复来调控AAA发病过程中异常的ECM代谢。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.