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

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


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.

MeSH terms

  • Animals
  • Cardiotonic Agents / metabolism*
  • Fetus / metabolism
  • Heart Failure / blood
  • Heart Failure / pathology
  • Heart Failure / physiopathology
  • Heart Function Tests
  • Humans
  • Mice, Transgenic
  • Myocardial Infarction / blood
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardium / metabolism*
  • Myocardium / pathology*
  • Oxidative Stress
  • Pyroglutamate Hydrolase / metabolism*
  • Pyrrolidonecarboxylic Acid / blood
  • Pyrrolidonecarboxylic Acid / metabolism*
  • Rats
  • Receptors, Estrogen / metabolism
  • Reperfusion Injury / blood
  • Reperfusion Injury / pathology
  • Reperfusion Injury / physiopathology
  • Sequence Analysis, RNA
  • Stress, Mechanical
  • Transcription, Genetic


  • Cardiotonic Agents
  • ERRalpha estrogen-related receptor
  • Receptors, Estrogen
  • Pyroglutamate Hydrolase
  • Pyrrolidonecarboxylic Acid