Universität zu Köln

Faller, Kiterie M. E., Atzler, Dorothee ORCID: 0000-0002-6551-1544, McAndrew, Debra J., Zervou, Sevasti, Whittington, Hannah J., Simon, Jillian N., Aksentijevic, Dunja ORCID: 0000-0002-8480-6727, ten Hove, Michiel, Choe, Chi-un, Isbrandt, Dirk, Casadei, Barbara, Schneider, Jurgen E., Neubauer, Stefan and Lygate, Craig A. (2018). Impaired cardiac contractile function in arginine:glycine amidinotransferase knockout mice devoid of creatine is rescued by homoarginine but not creatine. Cardiovasc. Res., 114 (3). S. 417 - 431. OXFORD: OXFORD UNIV PRESS. ISSN 1755-3245

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Abstract

Creatine buffers cellular adenosine triphosphate (ATP) via the creatine kinase reaction. Creatine levels are reduced in heart failure, but their contribution to pathophysiology is unclear. Arginine:glycine amidinotransferase (AGAT) in the kidney catalyses both the first step in creatine biosynthesis as well as homoarginine (HA) synthesis. AGAT(-/-) mice fed a creatine-free diet have a whole body creatine-deficiency. We hypothesized that AGAT(-/-) mice would develop cardiac dysfunction and rescue by dietary creatine would imply causality. Withdrawal of dietary creatine in AGAT(-/-) mice provided an estimate of myocardial creatine efflux of similar to 2.7%/day; however, n vivo cardiac function was maintained despite low levels of myocardial creatine. Using AGAT(-/-) mice naive to dietary creatine we confirmed absence of phosphocreatine in the heart, but crucially, ATP levels were unchanged. Potential compensatory adaptations were absent, AMPK was not activated and respiration in isolated mitochondria was normal. AGAT(-/-) mice had rescuable changes in body water and organ weights suggesting a role for creatine as a compatible osmolyte. Creatine-naive AGAT(-/-) mice had haemodynamic impairment with low LV systolic pressure and reduced inotropy, lusitropy, and contractile reserve. Creatine supplementation only corrected systolic pressure despite normalization of myocardial creatine. AGAT(-/-) mice had low plasma HA and supplementation completely rescued all other haemodynamic parameters. Contractile dysfunction in AGAT(-/-) was confirmed in Langendorff perfused hearts and in creatine-replete isolated cardiomyocytes, indicating that HA is necessary for normal cardiac function. Our findings argue against low myocardial creatine per se as a major contributor to cardiac dysfunction. Conversely, we show that HA deficiency can impair cardiac function, which may explain why low HA is an independent risk factor for multiple cardiovascular diseases.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Faller, Kiterie M. E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Atzler, Dorothee UNSPECIFIED orcid.org/0000-0002-6551-1544 UNSPECIFIED McAndrew, Debra J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zervou, Sevasti UNSPECIFIED UNSPECIFIED UNSPECIFIED Whittington, Hannah J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Simon, Jillian N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Aksentijevic, Dunja UNSPECIFIED orcid.org/0000-0002-8480-6727 UNSPECIFIED ten Hove, Michiel UNSPECIFIED UNSPECIFIED UNSPECIFIED Choe, Chi-un UNSPECIFIED UNSPECIFIED UNSPECIFIED Isbrandt, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Casadei, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, Jurgen E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Neubauer, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Lygate, Craig A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-194504
DOI:	10.1093/cvr/cvx242
Journal or Publication Title:	Cardiovasc. Res.
Volume:	114
Number:	3
Page Range:	S. 417 - 431
Date:	2018
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1755-3245
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GLYCINE AMIDINOTRANSFERASE; ARGININE/GLYCINE AMIDINOTRANSFERASE; MYOCARDIAL-INFARCTION; CARDIOVASCULAR RISK; ENERGY-METABOLISM; SKELETAL-MUSCLE; HEART-FAILURE; RAT HEARTS; PHOSPHOCREATINE; DEFICIENCY Multiple languages Cardiac & Cardiovascular Systems Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19450