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Published on: September 28, 2015
JNK2-MMP-9 axis facilitates the progression of intracranial aneurysms
Ryota Ishibashi1,2, Masahiko Itani1,3,4, Akitsugu Kawashima5
1Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Insights
The study identifies c-Jun N-terminal kinase (JNK) as a key factor in intracranial aneurysm (IA) progression. Inhibiting JNK may offer a new therapeutic strategy to prevent IA rupture and associated hemorrhagic strokes.
Area of Science:
- Vascular Biology
- Molecular Medicine
- Pathogenesis of Intracranial Aneurysms
Background:
- Intracranial aneurysms (IAs) pose a significant risk of subarachnoid hemorrhage, with poor patient outcomes.
- Matrix Metalloproteinases (MMPs) contribute to IA progression by degrading the extracellular matrix and weakening arterial walls.
- Identifying factors that regulate MMPs is crucial for developing novel therapeutic strategies against IA progression.
Purpose of the Study:
- To investigate the role of c-Jun N-terminal kinase (JNK) in the pathogenesis of intracranial aneurysms.
- To determine if JNK activation influences the expression of Matrix Metalloproteinases (MMPs) in IA lesions.
- To explore JNK as a potential therapeutic target for preventing IA progression and rupture.
Main Methods:
- Analysis of human IA lesion specimens to detect p-JNK expression in medial smooth muscle cells.
- Induction of IA in a rat model to study JNK activation during disease progression.
- Examination of downstream effects of JNK activation, including c-Jun and MMP-2/-9 expression.
- Genetic deletion of Jnk1 and Jnk2 in mice to assess their specific roles in IA development.
Main Results:
- Activated JNK (p-JNK) was detected in human IA lesions, primarily in medial smooth muscle cells.
- JNK activation in a rat IA model correlated with c-Jun activation and increased expression of MMP-2 and MMP-9.
- Genetic deletion of Jnk2, but not Jnk1, in mice significantly reduced IA incidence and suppressed MMP-2/-9 expression.
Conclusions:
- JNK plays a critical role in the progression of intracranial aneurysms by regulating MMP expression.
- Targeting JNK signaling represents a promising novel therapeutic strategy for preventing IA development and rupture.
- These findings provide new insights into IA pathogenesis and identify a potential therapeutic target.
Abstract:
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.
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