Oxytocin-Gly-Lys-Arg: a novel cardiomyogenic peptide.
BACKGROUND
Oxytocin (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.


RESULTS
High 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
These results raise the possibility that C-terminally extended OT molecules stimulate CM differentiation and contribute to heart growth during fetal life.
Research Centre, Centre Hospitalier de l'Université de Montréal - Hôtel-Dieu, Montreal, Quebec, Canada.
Bogdan A
BA
Danalache
Jolanta
J
Gutkowska
Magdalena J
MJ
Slusarz
Irena
I
Berezowska
Marek
M
Jankowski
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects*; D007150:Immunohistochemistry; D051379:Mice; D008958:Models, Molecular; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D034741:RNA, Small Interfering; D051381:Rats
D034741:RNA, Small Interfering; D010121:Oxytocin; C046278:oxytocin, Gly-Lys-Arg-