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

Atze van der Pol, Andres Gil, Herman H W Silljé, Jasper Tromp, Ekaterina S Ovchinnikova, Inge Vreeswijk-Baudoin, Martijn Hoes, Ibrahim J Domian, Bart van de Sluis, Jan M van Deursen, Adriaan A Voors, Dirk J van Veldhuisen, Wiek H van Gilst, Eugene Berezikov, Pim van der Harst, Rudolf A de Boer, Rainer Bischoff, Peter van der Meer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Scopus)

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 g-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.

Original languageEnglish
Article number8574
Number of pages11
JournalScience Translational Medicine
Volume9
Issue number415
DOIs
Publication statusPublished - 8-Nov-2017

Keywords

  • ESTROGEN-RELATED RECEPTOR
  • HEART-FAILURE PATIENTS
  • GENE-EXPRESSION
  • ANTIOXIDANT DEFENSES
  • PRESSURE-OVERLOAD
  • EJECTION FRACTION
  • GLUTATHIONE
  • DISEASE
  • GAMMA
  • PYROGLUTAMATE

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