OXYTOCIN, A NEW METABOLIC REGULATOR OF CARDIOMYOCYTES: PP.22.355

Abstract

Oxytocin (OT), originally believed to be a reproductive hormone, produced primarily in the hypothalamus, is also expressed in insulin-sensitive tissues, such as adipocytes, skeletal and cardiac muscles. We have recently uncovered the functional OT system, a peptide and its cognate receptor, in human and rat heart. In fetal and newborn hearts, OT exists mainly in its extended 3-amino-acid form, OT-Gly-Lys-Arg (OT-GKR). OT treatment improves the heart work in the experimental myocardial infarction. OT translocates glucose transporter, GLUT4 to the plasma membrane in human endothelial cells. Therefore, we hypothesized that the cardiac OT and OT-GKR system may be involved in the regulation of myocardial glucose uptake in physiological conditions and during metabolic stress, such as hypoxia (2, 4-dinitrophenol, DNP). Primary cultures of neonatal rat cardiomyocytes (CM) and cardiac progenitor cells expressing ABCG2 transporter (stem cell marker) were studied. In both cell types OT increased basal glucose uptake. In CM, OT (10 nM) increased glucose uptake to 4.0 ± 0.2 fmol/mg protein, with OT-GKR (10 nM) elevated it to 5.3 ± 0.4 fmol/mg protein (P < 0.001) in comparison to 2.2 fmol/mg in control cells. OT had a moderate synergistic effect with 0.1 mM DNP, augmenting basal glucose uptake to 5.5 ± 0.5 fmol/mg. OT-GKR (10 nM) was more potent in combination with DNP, increasing glucose uptake to 9.0 ± 1.0 fmol/mg. Wortmannin (0.1 ìM), an inhibitor of phosphatidylinositol-3-kinase, significantly suppressed the effect of OT and insulin (10 nM) (p < 0.001), indicating common pathways. STO-609 or Compound C, an AMPK inhibitor, blocked OT-induced glucose uptake in CM indicating the implication of Ca-CAMKK and AMPK in the process. The activation of AMPK increases glucose uptake in insulin-resistant CM. The ability of OT to stimulate the AMPK pathway points to possible therapeutic approaches in insulin resistance. Our data suggest that OT and OT-GKR influence glucose uptake in neonatal rat CM and can play an important role in the cardiac function and cell survival during metabolic stress.