Promoting endothelial function by S-nitrosoglutathione through the HIF-1α/VEGF pathway stimulates neurorepair and functional recovery following experimental stroke in rats.
Promoting endothelial function by S-nitrosoglutathione through the HIF-1α/VEGF pathway stimulates neurorepair and functional recovery following experimental stroke in rats.
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DOI：
10.2147/dddt.s77115
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Singh AK
中科院分区：
文献类型：
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作者：
Khan M;Dhammu TS;Matsuda F;Baarine M;Dhindsa TS;Singh I;Singh AK
对于中风患者，刺激神经修复机制是必要的，以减少发病率和残疾。我们以前对脑和脊髓损伤的研究表明，外源性治疗使用S-亚硝胺类药物S-亚硝基谷胱甘肽(人体内的一种一氧化氮和谷胱甘肽的代谢物)-刺激神经修复，有助于功能恢复。本研究采用大鼠脑缺血再灌注模型，验证了GSNO通过血管生成HIF-1α/血管内皮生长因子途径启动神经修复过程和改善神经行为功能的假说。成年雄性大鼠大脑中动脉闭塞60min后再灌流建立卒中模型。分别给予生理盐水(IR组，n=7)、GSNO(0.25 mg/kg，GSNO组，n=7)和GSNO+HIF-1α抑制剂2-甲氧基雌二醇(2-ME)(0.25 mg/kg GSNO+5.0 mg/kg 2-ME组，n=7)。对这些组进行了7天或14天的研究，以确定神经修复介质和功能恢复。脑毛细血管内皮细胞实验表明，GSNO促进血管生成，GSNO介导的血管内皮生长因子的诱导和血管生成的刺激依赖于HIF-1的α活性。与假手术组相比，缺血再灌注损伤可在一定程度上增加神经修复介质HIF-1、α、PECAM-1和血管标记物的表达，与神经行为功能明显受损相关。与IR相比，GSNO处理IR不仅能进一步增强缺氧诱导因子-1α、血管内皮生长因子和血管内皮细胞黏附分子-1的表达，而且还能改善功能。GSNO组的血管密度也高于IR组。在血管内皮细胞培养模型中，2-ME抑制缺氧诱导因子-1α后，血管内皮生长因子表达增加，GSNO诱导的血管形成程度降低。GSNO组的2-ME治疗不仅阻断了GSNO缩小脑梗塞体积、减少神经元丢失、增强PECAM-1表达的作用(P<；0.001)，而且还阻断了GSNO对运动和神经功能的改善(P<；0.001)。GSNO通过HIF-1依赖的α途径刺激神经修复过程，促进血管生成，帮助功能恢复，显示出治疗和翻译中风的前景。
For stroke patients, stimulating neurorepair mechanisms is necessary to reduce morbidity and disability. Our previous studies on brain and spinal cord trauma show that exogenous treatment with the S-nitrosylating agent S-nitrosoglutathione (GSNO) – a nitric oxide and glutathione metabolite of the human body – stimulates neurorepair and aids functional recovery. Using a rat model of cerebral ischemia and reperfusion (IR) in this study, we tested the hypothesis that GSNO invokes the neurorepair process and improves neurobehavioral functions through the angiogenic HIF-1α/VEGF pathway. Stroke was induced by middle cerebral artery occlusion for 60 minutes followed by reperfusion in adult male rats. The injured animals were treated with saline (IR group, n=7), GSNO (0.25 mg/kg, GSNO group, n=7), and GSNO plus the HIF-1α inhibitor 2-methoxyestra-diol (2-ME) (0.25 mg/kg GSNO + 5.0 mg/kg 2-ME, GSNO + 2-ME group, n=7). The groups were studied for either 7 or 14 days to determine neurorepair mediators and functional recovery. Brain capillary endothelial cells were used to show that GSNO promotes angiogenesis and that GSNO-mediated induction of VEGF and the stimulation of angiogenesis are dependent on HIF-1α activity. IR injury increased the expression of neurorepair mediators HIF-1α, VEGF, and PECAM-1 and vessel markers to a limited degree that correlate well with significantly compromised neurobehavioral functions compared with sham animals. GSNO treatment of IR not only remarkably enhanced further the expression of HIF-1α, VEGF, and PECAM-1 but also improved functioning compared with IR. The GSNO group also had a higher degree of vessel density than the IR group. Increased expression of VEGF and the degree of tube formation (angiogenesis) by GSNO were reduced after the inhibition of HIF-1α by 2-ME in an endothelial cell culture model. 2-ME treatment of the GSNO group also blocked not only GSNO’s effect of reduced infarct volume, decreased neuronal loss, and enhanced expression of PECAM-1 (P<0.001), but also its improvement of motor and neurological functions (P<0.001). GSNO stimulates the process of neurorepair, promotes angiogenesis, and aids functional recovery through the HIF-1α-dependent pathway, showing therapeutic and translational promise for stroke.