Wong Jamie K, Chen Lei, Huang Yong, Sehba Fatima A, Friedel Roland H, Zou Hongyan
Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States of America.
Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States of America.
PLoS One. 2015 Aug 28;10(8):e0136967. doi: 10.1371/journal.pone.0136967. eCollection 2015.
Stroke results in brain tissue damage from ischemia and oxidative stress. Molecular regulators of the protective versus deleterious cellular responses after cerebral ischemia remain to be identified. Here, we show that deletion of Smad1, a conserved transcription factor that mediates canonical bone morphogenetic protein (BMP) signaling, results in neuroprotection in an ischemia-reperfusion (I/R) stroke model. Uninjured mice with conditional deletion of Smad1 in the CNS (Smad1 cKO) displayed upregulation of the reactive astrocyte marker GFAP and hypertrophic morphological changes in astrocytes compared to littermate controls. Additionally, cultured Smad1(-/-) astrocytes exhibited an enhanced antioxidant capacity. When subjected to I/R injury by transient middle cerebral artery occlusion (tMCAO), Smad1 cKO mice showed enhanced neuronal survival and improved neurological recovery at 7 days post-stroke. This neuroprotective phenotype is associated with attenuated reactive astrocytosis and neuroinflammation, along with reductions in oxidative stress, p53 induction, and apoptosis. Our data suggest that Smad1-mediated signaling pathway is involved in stroke pathophysiology and may present a new potential target for stroke therapy.
中风会因缺血和氧化应激导致脑组织损伤。脑缺血后保护性与有害性细胞反应的分子调节因子仍有待确定。在此，我们表明，Smad1基因缺失可在缺血再灌注（I/R）中风模型中发挥神经保护作用，Smad1是一种介导经典骨形态发生蛋白（BMP）信号传导的保守转录因子。与同窝对照相比，中枢神经系统（CNS）中条件性缺失Smad1的未受伤小鼠（Smad1 cKO）表现出反应性星形胶质细胞标志物GFAP上调，且星形胶质细胞出现肥大形态变化。此外，培养的Smad1(-/-)星形胶质细胞表现出增强的抗氧化能力。通过短暂大脑中动脉闭塞（tMCAO）进行I/R损伤时，Smad1 cKO小鼠在中风后7天显示出增强的神经元存活能力和改善的神经功能恢复。这种神经保护表型与反应性星形胶质细胞增生和神经炎症减弱有关，同时氧化应激、p53诱导和细胞凋亡也减少。我们的数据表明，Smad1介导的信号通路参与中风病理生理学，可能是中风治疗的一个新的潜在靶点。
