精氨酸水平受 L-精氨酸：甘氨酸酰胺转移酶调节，并影响中风预后：来自人体和小鼠研究的结果。

Homoarginine levels are regulated by L-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies.

机构信息

Departments of Neurology (C.C., O.S., C.G., T.M.), Experimental Neuropediatrics (C.C., M.S., D.I.), Department of Clinical Pharmacology and Toxicology (D.A., R.H.B., N.L., R.A.B., E.S.), and German Center for Cardiovascular Research (D.A., P.S.W., R.H.B., S.B., T.Z., E.S.), Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (F.O., C.M., S. Baldus, S. Blankenberg, T.Z.); Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (T.S.); Department of Cardiology and Angiology (P.S.W.), Gutenberg Health Study (P.S.W.), and Department of Clinical Chemistry (K.L.), Johannes Gutenberg University, Mainz, Germany; Experimental Neurophysiology, University Hospital Cologne, Köln, Germany (D.I.); German Center for Neurodegenerative Diseases, Bonn, Germany (D.I.); Department of Clinical Pharmacy and Pharmacotherapy, Martin-Luther-University Halle Wittenberg, Halle Germany (R.A.B.); Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK (A.M.C., P.J.G.); Department of Radiology, Radboud University Medical Centre Nijmegen, Nijmegen, Netherlands (C.N., A.H.); and Laboratory of Neurochemistry and Behavior, Born-Bunge Foundation, University of Antwerp, Antwerp, Belgium (B.M., P.P. De D.).

出版信息

Circulation. 2013 Sep 24;128(13):1451-61. doi: 10.1161/CIRCULATIONAHA.112.000580. Epub 2013 Sep 4.

DOI:10.1161/CIRCULATIONAHA.112.000580

PMID:24004504

Abstract

BACKGROUND

Endogenous arginine homologues, including homoarginine, have been identified as novel biomarkers for cardiovascular disease and outcomes. Our studies of human cohorts and a confirmatory murine model associated the arginine homologue homoarginine and its metabolism with stroke pathology and outcome.

METHODS AND RESULTS

Increasing homoarginine levels were independently associated with a reduction in all-cause mortality in patients with ischemic stroke (7.4 years of follow-up; hazard ratio for 1-SD homoarginine, 0.79 [95% confidence interval, 0.64-0.96]; P=0.019; n=389). Homoarginine was also independently associated with the National Institutes of Health Stroke Scale+age score and 30-day mortality after ischemic stroke (P<0.05; n=137). A genome-wide association study revealed that plasma homoarginine was strongly associated with single nucleotide polymorphisms in the L-arginine:glycine amidinotransferase (AGAT) gene (P<2.1 × 10(-8); n=2806), and increased AGAT expression in a cell model was associated with increased homoarginine. Next, we used 2 genetic murine models to investigate the link between plasma homoarginine and outcome after experimental ischemic stroke: (1) an AGAT deletion (AGAT(-/-)) and (2) a guanidinoacetate N-methyltransferase deletion (GAMT(-/-)) causing AGAT upregulation. As suggested by the genome-wide association study, homoarginine was absent in AGAT(-/-) mice and increased in GAMT(-/-) mice. Cerebral damage and neurological deficits in experimental stroke were increased in AGAT(-/-) mice and attenuated by homoarginine supplementation, whereas infarct size in GAMT(-/-) mice was decreased compared with controls.

CONCLUSIONS

Low homoarginine appears to be related to poor outcome after ischemic stroke. Further validation in future trials may lead to therapeutic adjustments of homoarginine metabolism that alleviate stroke and other vascular disorders.

摘要

背景

内源性精氨酸类似物，包括同型精氨酸，已被确定为心血管疾病和结局的新型生物标志物。我们对人类队列和一个验证性的小鼠模型的研究表明，精氨酸类似物同型精氨酸及其代谢与中风病理和结果有关。

方法和结果

同型精氨酸水平的增加与缺血性中风患者的全因死亡率降低独立相关（7.4 年的随访；1-SD 同型精氨酸的危险比为 0.79[95%置信区间，0.64-0.96]；P=0.019；n=389）。同型精氨酸也与 NIH 中风量表+年龄评分和缺血性中风后 30 天死亡率独立相关（P<0.05；n=137）。全基因组关联研究显示，血浆同型精氨酸与 L-精氨酸：甘氨酸酰胺转移酶（AGAT）基因中的单核苷酸多态性强烈相关（P<2.1×10(-8)；n=2806），细胞模型中 AGAT 表达增加与同型精氨酸增加相关。接下来，我们使用 2 种遗传小鼠模型来研究实验性缺血性中风后血浆同型精氨酸与结局之间的联系：（1）AGAT 缺失（AGAT(-/-)）和（2）胍基乙酸 N-甲基转移酶缺失（GAMT(-/-)）导致 AGAT 上调。正如全基因组关联研究所表明的那样，AGAT(-/-)小鼠中不存在同型精氨酸，而 GAMT(-/-)小鼠中同型精氨酸增加。AGAT(-/-)小鼠实验性中风后的脑损伤和神经功能缺损增加，并通过同型精氨酸补充得到缓解，而 GAMT(-/-)小鼠的梗死面积与对照组相比减小。