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EV-3, an endogenous human erythropoietin isoform with distinct functional relevance.

ABSTRACT: Generation of multiple mRNAs by alternative splicing is well known in the group of cytokines and has recently been reported for the human erythropoietin (EPO) gene. Here, we focus on the alternatively spliced EPO transcript characterized by deletion of exon 3 (hEPO?3). We show co-regulation of EPO and hEPO?3 in human diseased tissue. The expression of hEPO?3 in various human samples was low under normal conditions, and distinctly increased in pathological states. Concomitant up-regulation of hEPO?3 and EPO in response to hypoxic conditions was also observed in HepG2 cell cultures. Using LC-ESI-MS/MS, we provide first evidence for the existence of hEPO?3 derived protein EV-3 in human serum from healthy donors. Contrary to EPO, recombinant EV-3 did not promote early erythroid progenitors in cultures of human CD34+ haematopoietic stem cells. Repeated intraperitoneal administration of EV-3 in mice did not affect the haematocrit. Similar to EPO, EV-3 acted anti-apoptotic in rat hippocampal neurons exposed to oxygen-glucose deprivation. Employing the touch-screen paradigm of long-term visual discrimination learning, we obtained first in vivo evidence of beneficial effects of EV-3 on cognition. This is the first report on the presence of a naturally occurring EPO protein isoform in human serum sharing non-erythropoietic functions with EPO.

SUBMITTER: Bonnas C

PROVIDER: S-EPMC5473850 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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EV-3, an endogenous human erythropoietin isoform with distinct functional relevance.

Bonnas Christel C Wüstefeld Liane L Winkler Daniela D Kronstein-Wiedemann Romy R Dere Ekrem E Specht Katja K Boxberg Melanie M Tonn Torsten T Ehrenreich Hannelore H Stadler Herbert H Sillaber Inge I

Scientific reports 20170616 1

Generation of multiple mRNAs by alternative splicing is well known in the group of cytokines and has recently been reported for the human erythropoietin (EPO) gene. Here, we focus on the alternatively spliced EPO transcript characterized by deletion of exon 3 (hEPOΔ3). We show co-regulation of EPO and hEPOΔ3 in human diseased tissue. The expression of hEPOΔ3 in various human samples was low under normal conditions, and distinctly increased in pathological states. Concomitant up-regulation of hEP ...[more]

PMID: 28623280

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Project description:BackgroundNew biomarkers that predict later neurodevelopmental morbidity are needed. This study evaluated the associations between umbilical cord serum erythropoietin (us-EPO) and neurodevelopmental morbidity by the age of 2-6.5 years in a Finnish cohort.MethodsThis study included 878 non-anomalous children born alive in 2012 to 2016 in Helsinki University Hospitals and whose us-EPO concentration was determined at birth. Data of these children were linked to data from the Finnish Medical Birth Register and the Finnish Hospital Discharge Register. Neurodevelopmental morbidity included cerebral palsy, epilepsy, intellectual disability, autism spectrum disorder, sensorineural defects, and minor neurodevelopmental disorders.ResultsIn the cohort including both term and preterm children, us-EPO levels correlated with gestational age (r = 0.526) and were lower in premature children. High us-EPO levels (>100 IU/l) were associated with an increased risk of severe neurodevelopmental morbidity (OR: 4.87; 95% CI: 1.05-22.58) when adjusted for the gestational age. The distribution of us-EPO levels did not differ in children with or without the later neurodevelopmental diagnosis.ConclusionsAlthough high us-EPO concentration at birth was associated with an increased risk of neurodevelopmental morbidity in early childhood, the role of us-EPO determination in clinical use appears to be minor.ImpactWe determined whether endogenous umbilical cord serum erythropoietin would be a new useful biomarker to predict the risk of neurodevelopmental morbidity. This study evaluated the role of endogenous erythropoietin at birth in neurodevelopmental morbidity with a study population of good size and specific diagnoses based on data from high-quality registers. Although high umbilical cord serum erythropoietin concentration at birth was associated with an increased risk of neurodevelopmental morbidity in early childhood, the clinical value of erythropoietin determination appears to be minor.

Dataset Information

EV-3, an endogenous human erythropoietin isoform with distinct functional relevance.

Publications

EV-3, an endogenous human erythropoietin isoform with distinct functional relevance.

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