Universität zu Köln

Choe, Chi-un, Atzler, Dorothee ORCID: 0000-0002-6551-1544, Wild, Philipp S., Carter, Angela M., Boeger, Rainer H., Ojeda, Francisco, Simova, Olga, Stockebrand, Malte, Lackner, Karl, Nabuurs, Christine, Marescau, Bart, Streichert, Thomas, Mueller, Christian, Lueneburg, Nicole, De Deyn, Peter P., Benndorf, Ralf A., Baldus, Stephan, Gerloff, Christian ORCID: 0000-0002-6484-8882, Blankenberg, Stefan, Heerschap, Arend, Grant, Peter J., Magnus, Tim, Zeller, Tanja ORCID: 0000-0003-3379-2641, Isbrandt, Dirk and Schwedhelm, Edzard (2013). Homoarginine Levels Are Regulated by L-Arginine: Glycine Amidinotransferase and Affect Stroke Outcome Results From Human and Murine Studies. Circulation, 128 (13). S. 1451 - 1462. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1524-4539

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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<2.1x10(-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Choe, Chi-un UNSPECIFIED UNSPECIFIED UNSPECIFIED Atzler, Dorothee UNSPECIFIED orcid.org/0000-0002-6551-1544 UNSPECIFIED Wild, Philipp S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Carter, Angela M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boeger, Rainer H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ojeda, Francisco UNSPECIFIED UNSPECIFIED UNSPECIFIED Simova, Olga UNSPECIFIED UNSPECIFIED UNSPECIFIED Stockebrand, Malte UNSPECIFIED UNSPECIFIED UNSPECIFIED Lackner, Karl UNSPECIFIED UNSPECIFIED UNSPECIFIED Nabuurs, Christine UNSPECIFIED UNSPECIFIED UNSPECIFIED Marescau, Bart UNSPECIFIED UNSPECIFIED UNSPECIFIED Streichert, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Lueneburg, Nicole UNSPECIFIED UNSPECIFIED UNSPECIFIED De Deyn, Peter P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Benndorf, Ralf A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Baldus, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Gerloff, Christian UNSPECIFIED orcid.org/0000-0002-6484-8882 UNSPECIFIED Blankenberg, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Heerschap, Arend UNSPECIFIED UNSPECIFIED UNSPECIFIED Grant, Peter J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Magnus, Tim UNSPECIFIED UNSPECIFIED UNSPECIFIED Zeller, Tanja UNSPECIFIED orcid.org/0000-0003-3379-2641 UNSPECIFIED Isbrandt, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwedhelm, Edzard UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-475696
DOI:	10.1161/CIRCULATIONAHA.112.000580
Journal or Publication Title:	Circulation
Volume:	128
Number:	13
Page Range:	S. 1451 - 1462
Date:	2013
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	1524-4539
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MASS-SPECTROMETRIC DETERMINATION; NITRIC-OXIDE; GUANIDINO COMPOUNDS; CARDIOVASCULAR RISK; MOUSE MODEL; BLOOD-FLOW; CREATINE; DEFICIENCY; BRAIN; SERUM Multiple languages Cardiac & Cardiovascular Systems; Peripheral Vascular Disease Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47569