Identification of Hic-5 as a novel molecule in the development of abdominal aortic aneurysms

活性氧（Reactive oxygen species， ROS）在腹主动脉瘤（aortic动脉瘤，AAA）的发病过程中起着关键作用。然而，ROS在AAA发病中的细胞信号传导的确切机制尚未完全阐明。过氧化氢诱导克隆5号（Hic-5）被鉴定为H2O2和tgfβ诱导基因。使用血管诱导的AAA小鼠模型，我们发现Hic-5-/-小鼠完全免受AAA形成的保护。Hic-5-/-小鼠表现出弹性板退化、主动脉扩张和破裂的减少。机制研究表明，Hic-5作为支架蛋白特异性地与JNK2及其上游MKK4相互作用，导致JNK2磷酸化并随之表达MMP2。Hic-5作为一种支架蛋白，专门用于激活JNK2通路，从而导致SMCs中MMPs的诱导和激活以及随后的AAA形成。因此，hic -5靶向治疗可能为未来AAA的治疗提供一种新的治疗选择。

Reactive oxygen species (ROS) play a key role in the pathogenesis of abdominal aortic aneurysm (AAA).However, the precise mechanism of cellular signaling by ROS in the pathogenesis of AAA has not been fully elucidated.Hydrogen peroxide-inducible clone 5 (Hic-5) was identified as a H2O2 and TGFbeta-inducible gene. Using the AngII-induced AAA mice model, we showed that Hic-5-/- mice were completely protected from AAA formation.Hic-5-/- mice show decreased elastic lamina degradation, aortic expansion and rupture. Mechanistic studies showed that Hic-5 interacts as a scaffold protein specifically with JNK2 and its upstream MKK4, resulting in the phosphorylation of JNK2 and consequent MMP2 expression. Hic-5 serves as a scaffold protein specifically for activating the JNK2 pathway, thereby leading to the induction and activation of MMPs in SMCs and subsequent AAA formation.Thus, Hic-5-targeted therapy may provide a novel therapeutic option for the treatment of AAA in the future.