Yan W, Zhao X, Chen H, Zhong D, Jin J, Qin Q, Zhang H, Ma S, Li G
Department of Neurology, the First Affiliated Hospital, Harbin Medical University, 23 You Zheng Street, Harbin, 150001 Heilongjiang, PR China.
Department of Neurology, the First Affiliated Hospital, Harbin Medical University, 23 You Zheng Street, Harbin, 150001 Heilongjiang, PR China.
Neuroscience. 2016 Jun 21;326:141-157. doi: 10.1016/j.neuroscience.2016.03.055. Epub 2016 Mar 31.
Dystroglycan (DG) is widely expressed in various tissues, and throughout the cerebral microvasculature. It consists of two subunits, α-DG and β-DG, and the cleavage of the latter by matrix metalloproteinase (MMP)-2 and -9 underlies a number of physiological and pathological processes. However, the involvement of MMP-2/-9-mediated β-DG cleavage in cerebral ischemia remains uncertain. In astrocytes, DG is crucial for maintaining the polarization of aquaporin-4 (AQP4), which plays a role in the regulation of cytotoxic and vasogenic edema. The present study aimed to explore the effects of MMP-2/-9-mediated β-DG cleavage on AQP4 polarization and brain edema in acute cerebral ischemia. A model of cerebral ischemia was established via permanent middle cerebral artery occlusion (pMCAO) in male C57BL/6 mice. Western blotting, real-time polymerase chain reaction (PCR), immunohistochemical staining, immunofluorescent staining, electron microscopy, and light microscopy were used. Captopril was applied as a selective MMP-2/-9 inhibitor. Recombinant mouse MMP (rmMMP)-2 and -9 were used in an in vitro cleavage experiment. The present study demonstrated evidence of β-DG cleavage by MMP-2/-9 in pMCAO mouse brains; this cleavage was implicated in AQP4 redistribution and brain edema in cerebral ischemia. In addition, captopril exacerbated cytotoxic edema and ameliorated vasogenic edema at 24h after pMCAO, and alleviated brain edema and neurological deficit at 48h and 72h. In conclusion, this study provides novel insight into the effects of MMP-2/-9-mediated β-DG cleavage in acute cerebral ischemia. Such findings might facilitate the development of a therapeutic strategy for the optimization of MMP-2/-9 targeted treatment in cerebral ischemia.
肌营养不良聚糖（DG）广泛表达于各种组织以及整个脑微血管系统中。它由两个亚基组成，即α-DG和β-DG，后者被基质金属蛋白酶（MMP）-2和-9切割是许多生理和病理过程的基础。然而，MMP-2/-9介导的β-DG切割在脑缺血中的作用仍不确定。在星形胶质细胞中，DG对于维持水通道蛋白4（AQP4）的极化至关重要，而AQP4在细胞毒性水肿和血管源性水肿的调节中发挥作用。本研究旨在探讨MMP-2/-9介导的β-DG切割对急性脑缺血中AQP4极化和脑水肿的影响。通过永久性大脑中动脉闭塞（pMCAO）在雄性C57BL/6小鼠中建立脑缺血模型。采用蛋白质免疫印迹法、实时聚合酶链反应（PCR）、免疫组织化学染色、免疫荧光染色、电子显微镜和光学显微镜等方法。使用卡托普利作为选择性MMP-2/-9抑制剂。在体外切割实验中使用重组小鼠MMP（rmMMP）-2和-9。本研究证明了在pMCAO小鼠脑中MMP-2/-9对β-DG的切割；这种切割与脑缺血中AQP4的重新分布和脑水肿有关。此外，卡托普利在pMCAO后24小时加剧了细胞毒性水肿并改善了血管源性水肿，并在48小时和72小时减轻了脑水肿和神经功能缺损。总之，本研究为MMP-2/-9介导的β-DG切割在急性脑缺血中的作用提供了新的见解。这些发现可能有助于制定一种治疗策略，以优化脑缺血中针对MMP-2/-9的靶向治疗。
