Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Neurosurgery, Medical Research Institute KITANO HOSPITAL, PIIF Tazuke-Kofukai, Osaka, Japan.
Sci Rep. 2024 Aug 21;14(1):19458. doi: 10.1038/s41598-024-70493-5.
Intracranial aneurysm (IA) can cause subarachnoid hemorrhage or some other hemorrhagic stroke after rupture. Because of the poor outcome in spite of the intensive medical care after the onset of hemorrhage, the development of a novel therapeutic strategy like medical therapy to prevent the progression of the disease becomes a social need. As the reduction of arterial stiffness due to the degeneration of the extracellular matrix via Matrix Metalloproteinases (MMPs) becomes one of the central machineries leading to the progression of IAs through a series of studies, factors regulating the expression or the activity of MMPs could be a therapeutic target. In the present study, specimens from human IA lesions and the animal model of IAs were used to examine the expression of c-Jun N-terminal kinase (JNK) which might exacerbate expressions of MMPs in the lesions to weaken arterial walls resulting in the progression of the disease. In some human IA lesions examined, the expression of p-JNK, the activated form of JNK, could be detected mostly in the medial smooth muscle cells. In IA lesions induced in rats, the activation of JNK was induced during the progression of the disease and accompanied with the activation of downstream transcriptional factor c-Jun and importantly with the expression of MMP-2 or -9. The genetic deletion of Jnk2, not Jnk1, in mice significantly prevented the incidence of IAs with the suppression of the expression of MMP-2 or MMP-9. These results combined together have suggested the crucial role of JNK in the progression of IAs through regulating the expression of MMPs. The results from the present study provides the novel insights about the pathogenesis of IA progression and also about the therapeutic target.
颅内动脉瘤（IA）破裂后可引起蛛网膜下腔出血或其他一些出血性中风。由于出血后尽管进行了强化医疗护理，但仍预后不良，因此需要开发新的治疗策略，如药物治疗来预防疾病进展，这成为一种社会需求。由于基质金属蛋白酶（MMPs）导致细胞外基质退化导致动脉僵硬的减少成为导致 IA 进展的核心机制之一，因此调节 MMPs 表达或活性的因素可能成为治疗靶点。在本研究中，使用来自人 IA 病变和 IA 动物模型的标本来检查 c-Jun N 末端激酶（JNK）的表达，该激酶可能加剧病变中 MMPs 的表达，从而削弱动脉壁，导致疾病进展。在检查的一些人 IA 病变中，活化形式的 JNK（p-JNK）的表达主要可在中膜平滑肌细胞中检测到。在大鼠诱导的 IA 病变中，JNK 的激活在疾病进展过程中诱导，并伴有下游转录因子 c-Jun 的激活，重要的是伴有 MMP-2 或 MMP-9 的表达。在小鼠中敲除 Jnk2（而非 Jnk1）可显著预防 IA 的发生，并抑制 MMP-2 或 MMP-9 的表达。这些结果共同表明 JNK 通过调节 MMPs 的表达在 IA 进展中起关键作用。本研究的结果提供了关于 IA 进展发病机制和治疗靶点的新见解。
