Abstract
BackgroundOxytocin (OT), synthesized in the heart, has the ability to heal injured hearts and to promote cardiomyogenesis from stem cells. Recently, we reported that the OT-GKR molecule, a processing intermediate of OT, potently increased the spontaneous formation of cardiomyocytes (CM) in embryonic stem D3 cells and augmented glucose uptake in newborn rat CM above the level stimulated by OT. In the present experiments, we investigated whether OT-GKR exists in fetal and newborn rodent hearts, interacts with the OT receptors (OTR) and primes the generation of contracting cells expressing CM markers in P19 cells, a model for the study of early heart differentiation.Methodology/Principal FindingsHigh performance liquid chromatography of newborn rat heart extracts indicated that OT-GKR was a dominant form of OT. Immunocytochemistry of mouse embryos (embryonic day 15) showed cardiac OT-GKR accumulation and OTR expression. Computerized molecular modeling revealed OT-GKR docking to active OTR sites and to V1a receptor of vasopressin. In embryonic P19 cells, OT-GKR induced contracting cell colonies and ventricular CM markers more potently than OT, an effect being suppressed by OT antagonists and OTR-specific small interfering (si) RNA. The V1a receptor antagonist and specific si-RNA also significantly reduced OT-GKR-stimulated P19 contracting cells. In comparison to OT, OT-GKR induced in P19 cells less α-actinin, myogenin and MyoD mRNA, skeletal muscle markers.Conclusions/SignificanceThese results raise the possibility that C-terminally extended OT molecules stimulate CM differentiation and contribute to heart growth during fetal life.
Highlights
Oxytocin (OT), recognized as a female reproductive hormone, is largely produced in hypothalamic magnocellular neurons of paraventricular and supraoptic nuclei
A minor peak was observed at k’ = 1.67, the point of OT-GK elution, and a minimal peak, if any, was detected at the point of elution of OT-G
The presence of OT-GKR in specific High pressure liquid chromatography (HPLC) fractions was confirmed by specific RIA with antibodies specific for OT and antibodies detecting OT-X forms
Summary
Oxytocin (OT), recognized as a female reproductive hormone, is largely produced in hypothalamic magnocellular neurons of paraventricular and supraoptic nuclei. OT-X forms have been detected in the developing brain of animals and in fetal plasma. The plasma OT-X elevation reported during early fetal development in sheep [3] is reduced in late gestation, when OT begins to predominate in the circulation. We reported that the OT-GKR molecule, a processing intermediate of OT, potently increased the spontaneous formation of cardiomyocytes (CM) in embryonic stem D3 cells and augmented glucose uptake in newborn rat CM above the level stimulated by OT. We investigated whether OT-GKR exists in fetal and newborn rodent hearts, interacts with the OT receptors (OTR) and primes the generation of contracting cells expressing CM markers in P19 cells, a model for the study of early heart differentiation
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