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精氨酸-甘氨酸氨甲酰基转移酶缺乏症小鼠脑中精氨酸和肌酸依赖性基因调控。

Homoarginine- and Creatine-Dependent Gene Regulation in Murine Brains with l-Arginine:Glycine Amidinotransferase Deficiency.

机构信息

University Heart and Vascular Centre Hamburg, Clinic for Cardiology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.

Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.

出版信息

Int J Mol Sci. 2020 Mar 9;21(5):1865. doi: 10.3390/ijms21051865.

DOI:10.3390/ijms21051865
PMID:32182846
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7084559/
Abstract

l-arginine:glycine amidinotransferase (AGAT) and its metabolites homoarginine (hArg) and creatine have been linked to stroke pathology in both human and mouse studies. However, a comprehensive understanding of the underlying molecular mechanism is lacking. To investigate transcriptional changes in cerebral AGAT metabolism, we applied a transcriptome analysis in brains of wild-type (WT) mice compared to untreated AGAT-deficient (AGAT) mice and AGAT mice with creatine or hArg supplementation. We identified significantly regulated genes between AGAT and WT mice in two independent cohorts of mice which can be linked to amino acid metabolism (, ), creatine metabolism (), cerebral myelination () and neuronal excitability (). While and showed regulation by hArg supplementation, and were creatine dependent. Additional regulated genes such as and need further evaluation of their influence on cerebral function. Experimental stroke models showed a significant regulation of and . Together, these results reveal that AGAT deficiency, hArg and creatine regulate gene expression in the brain, which may be critical in stroke pathology.

摘要

精氨酸-甘氨酸酰胺转移酶（AGAT）及其代谢产物同型精氨酸（hArg）和肌酸与人类和小鼠的中风病理有关。然而，其潜在的分子机制仍缺乏全面的了解。为了研究脑 AGAT 代谢的转录变化，我们对野生型（WT）小鼠的大脑进行了转录组分析，与未经处理的 AGAT 缺乏型（AGAT）小鼠以及用肌酸或 hArg 补充的 AGAT 小鼠进行了比较。我们在两个独立的小鼠队列中鉴定了 AGAT 和 WT 小鼠之间的差异表达基因，这些基因与氨基酸代谢（，）、肌酸代谢（）、脑髓鞘形成（）和神经元兴奋性（）有关。虽然和受 hArg 补充的调节，但和受肌酸的调节。其他受调控的基因，如和，需要进一步评估它们对大脑功能的影响。实验性中风模型显示和显著受调控。总之，这些结果表明 AGAT 缺乏、hArg 和肌酸调节大脑中的基因表达，这可能是中风病理的关键因素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a8d/7084559/dc605f0f284d/ijms-21-01865-g007.jpg
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