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Sci Transl Med. 2017 Nov 8;9(415). pii: eaam8574. doi: 10.1126/scitranslmed.aam8574.

Accumulation of 5-oxoproline in myocardial dysfunction and the protective effects of OPLAH.

Author information

1
Department of Cardiology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, Netherlands.
2
Department of Pharmacy, Analytical Biochemistry, University of Groningen, 9713 AV Groningen, Netherlands.
3
National Heart Centre Singapore, 169609 Singapore, Singapore.
4
European Research Institute for the Biology of Aging, Laboratory of Stem Cell Regulation and Mechanisms of Regeneration, University of Groningen, 9713 AV Groningen, Netherlands.
5
Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
6
Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
7
Molecular Genetics Section, Department of Pediatrics, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, Netherlands.
8
Department of Pediatrics, Mayo Clinic, Rochester, MN 55905, USA.
9
Department of Cardiology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, Netherlands. p.van.der.meer@umcg.nl.

Abstract

In response to heart failure (HF), the heart reacts by repressing adult genes and expressing fetal genes, thereby returning to a more fetal-like gene profile. To identify genes involved in this process, we carried out transcriptional analysis on murine hearts at different stages of development and on hearts from adult mice with HF. Our screen identified Oplah, encoding for 5-oxoprolinase, a member of the γ-glutamyl cycle that functions by scavenging 5-oxoproline. OPLAH depletion occurred as a result of cardiac injury, leading to elevated 5-oxoproline and oxidative stress, whereas OPLAH overexpression improved cardiac function after ischemic injury. In HF patients, we observed elevated plasma 5-oxoproline, which was associated with a worse clinical outcome. Understanding and modulating fetal-like genes in the failing heart may lead to potential diagnostic, prognostic, and therapeutic options in HF.

PMID:
29118264
DOI:
10.1126/scitranslmed.aam8574
[Indexed for MEDLINE]

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