Our results suggest that a reduction in lipid oxidation and an increase in lipogenesis are defective mechanisms leading to lipid accumulation in the liver of ovariectomized rats. We conclude that estrogen deficiency induced by ovariectomy changes the expression of genes that favor the development of a steatotic phenotype.

While an increasing amount of evidence demonstrates the homeostatic functions of the cardiac oxytocin (OT) system, less is known about the role of this hormone in the injured heart. The current study examined the effect of OT infusion on cell apoptosis, expression of proliferating cell nuclear antigen (PCNA) and inflammation in the acute and subacute phases of myocardial infarction (MI). Prior MI male Sprague-Dawley rats were infused subcutaneously with OT 25 or 125 ng/(kg h) for 3 or 7 days. Saline-treated MI and sham-operated rats served as controls. Echocardiography and analysis of cardiac sections were used to disclose OT actions. Left ventricular fractional shortening, estimated to be 46.0 +/- 1.8% in sham controls, declined to 21.1 +/- 3.3% in vehicle-treated MI rats and was improved to 34.2 +/- 2.1 and to 30.9 +/- 2.5% after treatment with OT 25 and 125 ng/(kg h), respectively. OT infusion resulted in: (1) increase of cells expressing PCNA in the infarct zone, diminished cell apoptosis and fibrotic deposits in the remote myocardium; (2) suppression of inflammation by reduction of neutrophils, macrophages and T lymphocytes; (3) depression of the expression of proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 with promotion of transforming growth factor-beta. OT treatment reduced expression of atrial and brain natriuretic peptides in the infarcted ventricle, as well as the concentration of both peptides in the circulation. These results indicate that continuous OT delivery reduces inflammation and apoptosis in infarcted and remote myocardium, thus improving function in the injured heart.

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 ...

Produced and released by the heart, oxytocin (OT) acts on its cardiac receptors to decrease the cardiac rate and force of contraction. We hypothesized that it might also be produced in the vasculature and regulate vascular tone. Consequently, we prepared acid extracts of the pulmonary artery and vena cava of male rats. OT concentrations in dog and sheep aortae were equivalent to those of rat aorta (2745 ؎ 180 pg͞mg protein), indicating that it is present in the vasculature of several mammalian species. Reverse-phase HPLC of aorta and vena cava extracts revealed a single peak corresponding to the amidated OT nonapeptide. Reverse-transcribed PCR confirmed OT synthesis in these tissues. Using the selective OT receptor ligand compound VI, we detected a high number of OT-binding sites in the rat vena cava and aorta. Furthermore, OT receptor (OTR) mRNA was found in the vena cava, pulmonary vein, and pulmonary artery with lower levels in the aorta, suggesting vessel-specific OTR distribution. The abundance of OTR mRNA in the vena cava and pulmonary vein was associated with high atrial natriuretic peptide mRNA. In addition, we have demonstrated that diethylstilbestrol treatment of immature female rats increased OT significantly in the vena cava but not in the aorta and augmented OTR mRNA in both the aorta (4-fold) and vena cava (2-fold), implying regulation by estrogen. Altogether, these data suggest that the vasculature contains an intrinsic OT system, which may be involved in the regulation of vascular tone as well as vascular regrowth and remodeling. O xytocin (OT), a neurophyseal hormone, is known to play a role in lactation and parturition and in the central nervous system as a neurotransmitter involved in sex and maternal behavior (1). The presence of equivalent amounts of plasma OT as well as a similar number of oxytocinergic neurons in males as in females suggests a more general physiological and endocrine role of this hormone. In this context, OT emerges as a regulator of natriuresis and blood volume.The mechanism of this regulation, which we proposed recently on the basis of blood volume expansion (VE) experiments in rats, involves OT release from the posterior pituitary gland into plasma, which is followed by atrial natriuretic peptide (ANP) release via activation of the OT receptors (OTRs) present in the heart (2). In effect, following blood VE, OT and ANP would produce a negative ionotropic and chronotropic response in the heart (3) that would rapidly reduce cardiac output and, thereby, effective circulating blood volume. Blood VE may also generate OT locally since the heart is a site of OT synthesis and OT secretion (4) as well as ANP secretion. Thus, the increased venous return to the heart following VE would stretch the cardiac myocytes activating OT release that would release ANP.Then, as has been shown recently, the natriuretic effects of VE in the kidney are caused in part by OT acting on its receptors in the renal tubules to generate NO, leading to increased cGMP; the increased plasma ANP acting on r...

In this study, semiquantitative reverse transcription-PCR analysis showed that estrogen receptor ␣ (ER␣) and ␤ (ER␤) mRNAs are developmentally regulated in the rat heart. We found that ER␣ mRNA was low in all heart chambers of 4-day-old rats, but was elevated in the atria (6-to 18-fold) and ventricles (3-to 4-fold) of adult rats. Western blotting analysis confirmed that these differences were efficiently translated into 67-kDa ER␣ protein. ER␤ mRNA was expressed at its highest level in the left atrium and was 3-to 4-fold lower in other heart chambers of 4-day-old animals. In adult rats ER␤ was decreased dramatically in the left atrium (20-fold) and, to a lesser extent in the other heart chambers (2-to 4-fold). Significant ER changes occurred already in the first week after birth. Accordingly, estrogen regulation in cells from neonatal hearts, as reported in several studies, may not correspond to that occurring in fully differentiated adult hearts, because of an altered degree of ER expression. In adult rats, ovariectomy decreases atrial ER␣, the atria͞body weight ratio, and atrial natriuretic peptide (ANP) transcription. Treatment of ovariectomized rats with 17-␤-estradiol (25 g, 10 days, s.c.) reversed these changes. In addition, there was no effect of ovariectomy and 17-␤-estradiol supplementation on systolic blood pressure, but in ovariectomized rats a decreased heart rate followed 17-␤-estradiol administration. Similar to the effects on ER␣ in the atria, ovariectomy lowered plasma ANP levels, and 17-␤-estradiol administration restored ANP in the plasma of ovariectomized rats. Changes in plasma ANP correlated with changes in ANP content in the right atrium, as demonstrated by RIA. Increased ANP expression and secretion in response to ER␣ activation may be a protective mechanism in the heart. A trial natriuretic peptide (ANP) is a cardiac hormone produced predominantly in heart atria (1). It acts primarily on the ANP A receptor, that is, guanylyl cyclase, which converts GTP to cGMP. cGMP mediates the actions of ANP via protein kinase G. ANP plays an integral role in the regulation of hydromineral homeostasis under normal and pathological conditions, through potent biological effects, including vasorelaxation, diuresis, natriuresis, and reduction of venous return by a shift of plasma into the interstitium. The natriuretic and diuretic actions of ANP result from enhanced glomerular filtration and͞or decreased tubular reabsorption of sodium and water, suppression of renin, aldosterone, and vasopressin secretion, as well as antagonism of most of the peripheral and central effects of angiotensin II. The heart not only secretes ANP but also expresses ANP receptors, which control heart functions through cGMP production in cardiomyocytes and fibroblasts (2).The ANP gene is strongly activated in response to hypertrophic stimuli in the heart and prevents hypertrophy by inhibition of protein synthesis in cardiac myocytes via a cGMP-dependent process (3). Mice lacking ANP or its guanylyl cyclase A receptor exhibit marked ...

Composite polymer electrolyte membranes are fabricated by the incorporation of Li 10 SnP 2 S 12 into the poly(ethylene oxide) (PEO) matrix using a solution-casting method. The incorporation of Li 10 SnP 2 S 12 plays a positive role on Li-ionic conductivity, mechanical property, and interfacial stability of the composite electrolyte and thus significantly enhances the electrochemical performance of the solid-state Li−S battery. The optimal PEO−1%Li 10 SnP 2 S 12 electrolyte presents a maximum ionic conductivity of 1.69 × 10 −4 S cm −1 at 50 °C and the highest mechanical strength. The possible mechanism for the enhanced electrochemical performance and mechanical property is analyzed. The uniform distribution of Li 10 SnP 2 S 12 in the PEO matrix inhibits crystallization and weakens the interactions among the PEO chains. The PEO− 1%Li 10 SnP 2 S 12 electrolyte exhibits lower interfacial resistance and higher interfacial stability with the lithium anode than the pure PEO/LiTFSI electrolyte. The Li−S cell comprising the PEO−1%Li 10 SnP 2 S 12 electrolyte exhibits outstanding electrochemical performance with a high discharge capacity (ca. 1000 mA h g −1 ), high Coulombic efficiency, and good cycling stability at 60 °C. Most importantly, the PEO−1%Li 10 SnP 2 S 12 -based cell possesses attractive performance with a high specific capacity (ca. 800 mA h g −1 ) and good cycling stability even at 50 °C, whereas the PEO/LiTFSI-based cell cannot be successfully discharged because of the low ionic conductivity and high interfacial resistance of the PEO/LiTFSI electrolyte.

All-solid-state lithium−sulfur batteries (ASSLSBs) have attracted great attention due to their inherent ability to eliminate the two critical issues (polysulfide shuttle effect and safety) of traditional liquid electrolyte based Li−S batteries. However, it remains a huge challenge for ASSLSBs to achieve high areal active mass loading and high active material utilization simultaneously due to the insulating nature of sulfur and Li 2 S, and the large volume change during cycling. Herein, a Li 2 S@C nanocomposite with Li 2 S nanocrystals uniformly embedded in conductive carbon matrix, is in situ generated by the combustion of lithium metal with CS 2 . Benefiting from its unique architecture, the Li 2 S@C exhibits exceptional electrochemical performance as cathode for ASSLSBs, with both ultrahigh areal Li 2 S loading (7 mg cm −2 ) and 91% of Li 2 S utilization (corresponding to a reversible capacity of 1067 mAh g −1 ). Moreover, the Li 2 S@C also possesses outstanding rate capability and cycling stability. High reversible capacity of 644 mAh g −1 is delivered at 2 mA cm −2 even after 700 cycles. This work demonstrates that ASSLSBs with superior electrochemical performance can be realized via rational design of the cathode structure, which provides a promising prospect to the development of ASSLSBs with practical energy density surpassing that of lithium ion batteries.

Oxytocin (OT), a hormone recently identified in the heart, induces embryonic and cardiac somatic stem cells to differentiate into cardiomyocytes (CM), possibly through nitric oxide (NO). We verified this hypothesis using P19 cells and P19 Clone 6 derivatives expressing a green fluorescent protein (GFP) reporter linked to cardiac myosin light chain-2v promoter. OT treatment of these cells induced beating cell colonies that were fully inhibited by N,G-nitro-L-argininemethyl-ester (L-NAME), an inhibitor of NO synthases (NOS), partially reduced by 1400W, an inhibitor of inducible NOS, and ODQ, an inhibitor of NO-sensitive guanylyl cyclases. The NO generator S-nitroso-N-acetylpenicillamine (SNAP) reversed the L-NAME inhibition of cell beating and GFP expression. In OT-induced cells, L-NAME significantly decreased transcripts of the cardiac markers Nkx2.5, MEF2c, ␣-myosin heavy chain, and less, GATA4, endothelial NOS, and atrial natriuretic peptide, as well as the skeletal myocyte (SM) marker myogenin. Image analysis of OT-induced P19Cl6-GFP cells revealed ventricular CM coexpressing sarcomeric ␣-actinin and GFP, with some cells exclusively expressing ␣-actinin, most likely of the SM phenotype. The OT-mediated production of CM, but not SM, was diminished by L-NAME. In P19 cells, exogenously added OT stimulated the expression of its own transcript, which was reduced in the presence of L-NAME. Surprisingly, L-NAME alone decreased the expression of anti-stage specific embryonic antigen-1 marker of the undifferentiated state and induced some beating colonies as well as GFP in P19Cl6-GFP cells. Collectively, our data suggest that the pleiotropic action of NO is involved in the initiation of CM differentiation of P19 cells and maintenance of their undifferentiated state. STEM CELLS 2007;25:679 -688