Research ArticleHeart Failure

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

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Science Translational Medicine  08 Nov 2017:
Vol. 9, Issue 415, eaam8574
DOI: 10.1126/scitranslmed.aam8574

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A fetal gene for heart failure

One way the heart responds to cardiac injury is by reverting gene expression to developmental patterns. Van der Pol et al. discovered that Oplah, a gene encoding an enzyme that converts 5-oxoproline to glutamate as part of the γ-glutamyl cycle, was repressed in adult mouse hearts with heart failure. Depleting Oplah in cardiomyocytes increased 5-oxoproline and oxidative stress, and elevated 5-oxoproline in blood samples from patients with heart failure was associated with worse outcome. Overexpressing OPLAH protected mice from cardiac injury in models of heart failure, suggesting that OPLAH and other fetal-like genes could be therapeutic targets.

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.

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