Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
J Neurochem. 2010 Oct;115(2):385-98. doi: 10.1111/j.1471-4159.2010.06933.x. Epub 2010 Aug 25.
The extracellular matrix (ECM) is important for both structural integrity and functions of the brain. Matrix metalloproteinases (MMPs) play major roles in ECM-remodeling under both physiological and pathological conditions. Reversion-inducing cysteine-rich protein with Kazal motifs (Reck) is a membrane-anchored MMP-regulator implicated in coordinated regulation of pericellular proteolysis. Although patho-physiological importance of MMPs and another group of MMP-regulators, tissue inhibitor of metalloproteinases, in brain ischemia has been demonstrated, little is known about the role of Reck in this process. In this study, we found that Reck is up-regulated in hippocampus and penumbra of subventricular zone after transient cerebral ischemia in mice. Most of the Reck-positive cells found at day 2 after ischemia are positive for Nestin as well as Ki67 and localized to the CA2 region of the hippocampus. At day 7 after ischemia, the Reck-positive cells increased in number, extended processes, expressed the reactive astrocyte marker GFAP and the neuronal marker NF200, and were widely distributed in the hippocampus. In the mutant mice carrying single functional Reck allele (Reck+/-), tissue damage and cell death after cerebral ischemia were augmented, the recovery of long-term potentiation in the hippocampus was compromised, NR2C subunit of NMDA receptor was up-regulated, gelatinolytic activity of MMPs were up-regulated and laminin-immunoreactivity was reduced. Our data implicate Reck in protection of ECM/tissue integrity and promotion of functional recovery in the brain after transient cerebral ischemia.
细胞外基质（ECM）对于大脑的结构完整性和功能都很重要。基质金属蛋白酶（MMPs）在生理和病理条件下都在 ECM 重塑中发挥主要作用。富含半胱氨酸的 Kazal 基序的反转诱导蛋白（Reck）是一种膜锚定的 MMP 调节剂，参与细胞周围蛋白水解的协调调节。尽管 MMPs 和另一组 MMP 调节剂——金属蛋白酶组织抑制剂在脑缺血中的病理生理重要性已经得到证实，但关于 Reck 在这一过程中的作用知之甚少。在这项研究中，我们发现 Reck 在小鼠短暂性脑缺血后的侧脑室下区海马体和半影区上调。缺血后第 2 天发现的 Reck 阳性细胞大多数为巢蛋白（Nestin）、Ki67 阳性，并定位于海马体 CA2 区。缺血后第 7 天，Reck 阳性细胞数量增加，突起延伸，表达反应性星形胶质细胞标志物 GFAP 和神经元标志物 NF200，并广泛分布于海马体。在携带单个功能性 Reck 等位基因（Reck+/-）的突变小鼠中，脑缺血后的组织损伤和细胞死亡加剧，海马体长时程增强的恢复受到损害，NMDA 受体 NR2C 亚基上调，MMP 的明胶酶活性上调，层粘连蛋白免疫反应性降低。我们的数据表明 Reck 参与了对 ECM/组织完整性的保护，并促进了短暂性脑缺血后大脑的功能恢复。
