Laaksamo Elisa, Tulamo Riikka, Baumann Marc, Dashti Reza, Hernesniemi Juha, Juvela Seppo, Niemelä Mika, Laakso Aki
Biomedicum Helsinki, Helsinki University Central Hospital, Helsinki, Finland.
Stroke. 2008 Mar;39(3):886-92. doi: 10.1161/STROKEAHA.107.497875. Epub 2008 Jan 31.
Mitogen-activated protein kinases (MAPKs) are involved in vascular wall remodeling, but their role in the pathogenesis of intracranial aneurysms (IAs) is poorly known. We investigated the expression and phosphorylation of the 3 major mitogen-activated protein kinases, c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase, in unruptured and ruptured human IAs.
Tissue samples (n=24, 12 unruptured and 12 ruptured IAs) were obtained during microneurosurgical clipping. The localization of the proteins was studied by immunofluorescent staining, and protein levels and phosphorylation state were studied by Western blotting.
The phosphorylation of p54 JNK was increased 1.5-fold in ruptured IAs and the phospho-p54 JNK level and its phosphorylation state directly correlated with IA size. The levels of phosphorylated and total levels of p38 were associated with IA size as well. Extracellular signal-regulated kinase did not associate with IA size or rupture status. Expression of transcription factor c-Jun, a downstream target of JNK, correlated with p54 JNK level and phosphorylation state. Furthermore, the levels of matrix metalloproteinase 9, known to have a role in vessel wall degeneration, correlated with p54 JNK phosphorylation in unruptured IAs and its expression was increased 4.3-fold in ruptured IAs.
Our results suggest that JNK activity and expression are involved in IA growth and possibly rupture and p38 expression in IA growth. Thus, pharmacological therapy affecting the stress-activated mitogen-activated protein kinases, JNK and p38, may enhance the repair of the IA wall in the future.
丝裂原活化蛋白激酶（MAPKs）参与血管壁重塑，但其在颅内动脉瘤（IAs）发病机制中的作用尚不清楚。我们研究了3种主要丝裂原活化蛋白激酶，即c-Jun氨基末端激酶（JNK）、p38和细胞外信号调节激酶，在未破裂和破裂的人类颅内动脉瘤中的表达及磷酸化情况。
在显微神经外科夹闭手术中获取组织样本（n = 24，12个未破裂颅内动脉瘤和12个破裂颅内动脉瘤）。通过免疫荧光染色研究蛋白的定位，通过蛋白质印迹法研究蛋白水平及磷酸化状态。
在破裂的颅内动脉瘤中，p54 JNK的磷酸化增加了1.5倍，磷酸化p54 JNK水平及其磷酸化状态与颅内动脉瘤大小直接相关。p-38的磷酸化水平和总水平也与颅内动脉瘤大小有关。细胞外信号调节激酶与颅内动脉瘤大小或破裂状态无关。转录因子c-Jun作为JNK的下游靶点，其表达与p54 JNK水平及磷酸化状态相关。此外，已知在血管壁退变中起作用的基质金属蛋白酶9的水平，在未破裂颅内动脉瘤中与p54 JNK磷酸化相关，在破裂颅内动脉瘤中其表达增加了4.3倍。
我们的结果表明，JNK活性和表达参与颅内动脉瘤的生长，并可能与破裂有关，而p38表达与颅内动脉瘤生长有关。因此，影响应激激活的丝裂原活化蛋白激酶JNK和p38的药物治疗，未来可能会增强颅内动脉瘤壁的修复。
