Previous studies demonstrated the presence of oxytocin (OT) and oxytocin receptors (OTRs) in the heart. The present work provides results supporting a potential role of OT in cardiomyogenesis. Here, we show a maximal OT and OTR protein level in the developing rat heart at day 21 of gestation and postnatal days 1-4, when cardiac myocytes are at a stage of intense hyperplasia. Between postnatal days 1 and 66, OT decreased linearly in all heart chambers (4.1-to 6.6-fold). Correspondingly, immunocytochemistry demonstrated that OTRs, which were eminent in postnatal cardiomyocytes, declined with age to low levels in adults. Interestingly, in coronary vasculature, OTRs developed in endothelial cells at postnatal days 12 and 22 and achieved a plateau in adult rats. These findings suggest that OT can be involved in developmental formation of the coronary vessels. In vivo, the OT͞OTR system in the fetal heart was sensitive to the actions of retinoic acid (RA), recognized as a major cardiac morphogen. RA treatment produced a significant increase (2-to 3-fold) both in the OT concentration and in the OT mRNA levels. Ex vivo, an OT antagonist inhibited RA-mediated cardiomyocyte differentiation of P19 embryonic stem cells. The decline of cardiac OT expression from infancy to adulthood of the rat and changes in cell types expressing OTR indicate a dynamic regulation of the OT system in the heart rather than constitutive expression. The results support the hypothesis that RA induces cardiomyogenesis by activation of the cardiac OT system. heart development ͉ oxytocin receptors ͉ retinoic acid ͉ oxytocin antagonist ͉ cardiomyocyte differentiation O xytocin (OT), recognized traditionally as a reproductive hormone with a major role in childbirth and lactation, is produced in high concentrations in the hypothalamic supraoptic nucleus and paraventricular nucleus, then transported from these source nuclei to the posterior pituitary by neurosecretion (1). Longitudinal studies of neural and hormonal circuits activated by experimental volume expansion have identified OT as a major regulator of cardiovascular functions (reviewed in refs. 2 and 3). OT, injected peripherally, causes a decrease of arterial pressure (4) while reducing both heart rate and the force of contractions in isolated atria (5). OT acts via neuroendocrine͞ endocrine͞paracrine pathways to release atrial natriuretic peptide (ANP) from the heart (6, 7). ANP is a potent diuretic, natriuretic, and vasorelaxant hormone that is also involved in cell growth regulation. In addition, we have demonstrated that in isolated, perfused hearts, an OT antagonist (OTA) blocks basal ANP release (7), suggesting the presence of local OT in the heart. Further study revealed cardiac OT synthesis (8), with OT being detected in the medium of cultured neonatal rat cardiomyocytes (9).Recently, we showed that P19 embryonic carcinoma cells, a model of mouse embryonic stem cells, express OT receptors (OTRs), and OT stimulates the differentiation of these cells into beating cell colonies expressing ...

The pleiotropic effects of retinoids are mediated by two families of nuclear receptors: RAR (retinoic acid receptors) and RXR (retinoid X receptors). 9-cis-Retinoic acid is a specific ligand for RXR receptors, whereas either 9-cis- or all-trans-retinoic acid activates the RAR receptor family. The existence of RXRs suggests a new role for isomerization in the biology of retinoic acid. We report here the identification of an aldehyde dehydrogenase in the rat kidney that catalysed the oxidation of 9-cis- and all-trans-retinal to corresponding retinoic acids with high efficiency, 9-cis-retinal being 2-fold more active than all-trans-retinal. Based on several criteria, such as amino acid sequence, pH optimum, and inhibition by chloral hydrate, this enzyme was found to be a novel isoenzyme of aldehyde dehydrogenase. 9-cis-Retinol, the precursor for the biosynthesis of 9-cis-retinal was identified in the rat kidney. The occurrence of endogenous 9-cis-retinol and the existence of specific dehydrogenase which participates in the catalysis of 9-cis-retinal suggest that all-trans-retinoi(d) isomerization to 9-cis-retinoi(d) occurs at the retinol level, analogous to all-trans-retinol isomerization to 11-cis-retinol in the visual cycle.

Recent investigations have demonstrated that elevated serum retinol-binding protein 4 (RBP4) secreted from adipose tissue plays a role in the development of systemic insulin resistance, and lowering RBP4 improves insulin sensitivity. These observations provide a rationale for the development of new antidiabetic agents aimed at reducing serum RBP4 concentrations. In this study, we sought to determine whether retinoic acid (RA) administration decreases serum RBP4 and suppresses insulin resistance in diabetic ob/ob mice. All-trans RA [100 mug/(moused) in corn oil] was administered by stomach intubation to a group of ob/ob mice, with the control group receiving the vehicle for 16 d. Body weight and food intake were monitored. Glucose and insulin tolerance tests were performed. We quantified serum RBP4 and retinol by Western blotting and HPLC, respectively. RA treatment reduced body weight (P < 0.05), basal serum glucose (P < 0.001), serum retinol (P < 0.01), and RBP4 (P < 0.05). It improved insulin sensitivity and decreased the retinol:RBP4 ratio (P < 0.05). These studies suggest that RA is an effective antidiabetic agent that could be considered in the treatment of type 2 diabetes.