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首页> 外文期刊>Journal of Cellular Physiology >Activation of GABA-A receptor ameliorates homocysteine-induced MMP-9 activation by ERK pathway.
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Activation of GABA-A receptor ameliorates homocysteine-induced MMP-9 activation by ERK pathway.

机译：激活受体-改善homocysteine-induced MMP-9通过ERK激活途径。

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摘要

Hyperhomocysteinemia (HHcy) is a risk factor for neuroinflammatory and neurodegenerative diseases. Homocysteine (Hcy) induces redox stress, in part, by activating matrix metalloproteinase-9 (MMP-9), which degrades the matrix and leads to blood-brain barrier dysfunction. Hcy competitively binds to gamma-aminbutyric acid (GABA) receptors, which are excitatory neurotransmitter receptors. However, the role of GABA-A receptor in Hcy-induced cerebrovascular remodeling is not clear. We hypothesized that Hcy causes cerebrovascular remodeling by increasing redox stress and MMP-9 activity via the extracellular signal-regulated kinase (ERK) signaling pathway and by inhibition of GABA-A receptors, thus behaving as an inhibitory neurotransmitter. Hcy-induced reactive oxygen species production was detected using the fluorescent probe, 2'-7'-dichlorodihydrofluorescein diacetate. Hcy increased nicotinamide adenine dinucleotide phosphate-oxidase-4 concomitantly suppressing thioredoxin. Hcy caused activation of MMP-9, measured by gelatin zymography. The GABA-A receptor agonist, muscimol ameliorated the Hcy-mediated MMP-9 activation. In parallel, Hcy caused phosphorylation of ERK and selectively decreased levels of tissue inhibitors of metalloproteinase-4 (TIMP-4). Treatment of the endothelial cell with muscimol restored the levels of TIMP-4 to the levels in control group. Hcy induced expression of iNOS and decreased eNOS expression, which lead to a decreased NO bioavailability. Furthermore muscimol attenuated Hcy-induced MMP-9 via ERK signaling pathway. These results suggest that Hcy competes with GABA-A receptors, inducing the oxidative stress transduction pathway and leading to ERK activation.
机译：半胱氨酸(HHcy)是一个风险因素神经炎症和神经退行性疾病。同型半胱氨酸(Hcy)诱导氧化还原压力,在某种程度上,通过激活矩阵metalloproteinase-9 (MMP-9),这削弱了矩阵并导致血脑屏障功能障碍。竞争性结合gamma-aminbutyric酸(GABA)受体,兴奋性神经递质受体。- Hcy-induced脑血管装修还不清楚。引起脑血管重构通过增加通过氧化还原压力和MMP-9活动细胞外signal-regulated激酶(ERK)信号通路抑制-受体,从而抑制行为神经递质。种生产检测使用荧光探针,2 ' 7 ' -dichlorodihydrofluorescein二醋酸盐。增加烟酰胺腺嘌呤二核苷酸phosphate-oxidase-4与此同时抑制硫氧还蛋白。以明胶zymography。受体激动剂,muscimol改善Hcy-mediated MMP-9激活。的磷酸化ERK和选择性造成的组织抑制剂的水平下降metalloproteinase-4 (TIMP-4)。内皮细胞与muscimol恢复了TIMP-4水平在对照组水平。Hcy伊诺和减少以挪士的诱导表达表达式,它导致没有下降生物利用度。Hcy-induced MMP-9通过ERK信号通路。这些结果表明,Hcy竞争-受体,诱发氧化应激转导通路,导致兵激活。

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