Accumulation of 5-oxoproline in myocardial dysfunction and the protective effects of OPLAH.
Atze van der PolAndres GilHerman H W SilljéJasper TrompEkaterina S OvchinnikovaInge Vreeswijk-BaudoinMartijn HoesIbrahim J DomianBart van de SluisJan M van DeursenAdriaan A VoorsDirk J van VeldhuisenWiek H van GilstEugene BerezikovPim van der HarstRudolf A de BoerRainer BischoffPeter Van der MeerPublished in: Science translational medicine (2018)
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.
Keyphrases
- heart failure
- acute heart failure
- genome wide
- genome wide identification
- left ventricular
- oxidative stress
- transcription factor
- end stage renal disease
- genome wide analysis
- bioinformatics analysis
- ejection fraction
- newly diagnosed
- atrial fibrillation
- chronic kidney disease
- dna methylation
- cell proliferation
- ischemia reperfusion injury
- prognostic factors
- dna damage
- peritoneal dialysis
- high throughput
- copy number
- signaling pathway
- cardiac resynchronization therapy
- adipose tissue
- heat shock
- skeletal muscle
- wild type
- metabolic syndrome