Leptin modulates nitric oxide production and lipid metabolism in human placenta

2006 ◽  
Vol 18 (4) ◽  
pp. 425 ◽  
Author(s):  
Verónica White ◽  
Elida González ◽  
Evangelina Capobianco ◽  
Carolina Pustovrh ◽  
Nora Martínez ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lipid Metabolism ◽  
Human Placenta ◽  
De Novo ◽  
Primary Cultures ◽  
Lipid Synthesis ◽  
No Production ◽  
Dependent Manner ◽  
Lipid Catabolism

Leptin has significant effects on appetite, energy expenditure, lipid mobilisation and reproduction. During pregnancy, leptin is produced in the placenta, a tissue in which leptin receptors are highly expressed, suggesting autocrine/paracrine functions for this hormone. In the present study, a putative role of leptin as a regulator of nitric oxide (NO) production and lipid metabolism was evaluated in term human placenta. We demonstrated that leptin enhanced NO production in human placental explants (P < 0.01). Although leptin did not modify the placental levels of cholesteryl esters and phospholipids, leptin decreased levels of triglycerides (P < 0.01) and cholesterol (P < 0.001) in term human placenta. The effect of leptin on lipid mass seems to be independent of the modulation of de novo lipid synthesis because leptin did not modify the incorporation of 14C-acetate into any of the lipids evaluated. We investigated the effects of leptin on placental lipid catabolism and found that in both term human placental explants and primary cultures of trophoblastic cells, leptin increased glycerol release, an index of the hydrolysis of esterified lipids, in a dose-dependent manner. In conclusion, we have shown that leptin affects NO production and lipid catabolism in human placenta, providing supportive evidence for a role of leptin in placental functions that would determine the transfer of nutrients to the developing fetus.

Modulatory effect of leptin on nitric oxide production and lipid metabolism in term placental tissues from control and streptozotocin-induced diabetic rats

2004 ◽  
Vol 16 (3) ◽  
pp. 363 ◽  
Author(s):  
Verónica White ◽  
Elida González ◽  
Evangelina Capobianco ◽  
Carolina Pustovrh ◽  
Carlos Soñez ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lipid Metabolism ◽  
De Novo ◽  
Lipid Synthesis ◽  
Placental Tissue ◽  
Diabetic Rats ◽  
Late Gestation ◽  
Diabetic Rat ◽  
No Production

Leptin production by placental tissues contributes to its circulating levels and functions. The diabetic pathology induces alterations in leptin levels. In the present study, leptin levels were evaluated in placental tissue from control and neonatal streptozotocin-induced (n-STZ) diabetic rats during late gestation. The effects of leptin levels on the generation of nitric oxide (NO), prostaglandin (PG) E2 production and lipid metabolism were examined. Leptin levels were diminished in placentas from n-STZ diabetic rats compared with controls (P < 0.01). These differences were also evident when leptin was evaluated immunohistochemically. Addition of leptin (1 nm) in vitro enhanced NO production in control (66%) and diabetic placentas (134%) by stimulating NO synthase activity (by 38% and 54%, respectively). The addition of leptin increased PGE2 production in placentas from control (173%) and diabetic rats (83%) and produced a 50% decrease in placental lipid levels (phospholipids, triacylglycerides, cholesterol and cholesteryl ester) without involving a reduction in de novo lipid synthesis. These data indicate that leptin enhances the production of placental NO and PGE2, vasoactive agents that modify placental blood flow, and that leptin stimulates placental lipid metabolism, probably generating more lipids for transfer to the fetus. In the diabetic rat, placental leptin was reduced, probably as a response to the maternal environment to locally regulate the transfer of nutrients to the developing fetus.

Role of G proteins in shear stress-mediated nitric oxide production by endothelial cells

1994 ◽  
Vol 267 (3) ◽  
pp. C753-C758 ◽  
Author(s):  
M. J. Kuchan ◽  
H. Jo ◽  
J. A. Frangos
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Shear Stress ◽  
G Protein ◽  
G Proteins ◽  
No Production ◽  
Dependent Manner ◽  
Protein Activation ◽  
Synthase Inhibitor

Exposure of cultured endothelial cells to shear stress resulting from well-defined fluid flow stimulates the production of nitric oxide (NO). We have established that an initial burst in production is followed by sustained steady-state NO production. The signal transduction events leading to this stimulation are not well understood. In the present study, we examined the role of regulatory guanine nucleotide binding proteins (G proteins) in shear stress-mediated NO production. In endothelial cells not exposed to shear stress, AIF4-, a general activator of G proteins, markedly elevated the production of guanosine 3',5'-cyclic monophosphate (cGMP). Pretreatment with NO synthase inhibitor N omega-nitro-L-arginine completely blocked this stimulation. Incubation with guanosine 5'-O-(2-thiodiphosphate) (GDP beta S), a general G protein inhibitor, blocked the flow-mediated burst in cGMP production in a dose-dependent manner. Likewise, GDP beta S inhibited NOx (NO2 + NO3) production for the 1st h. However, inhibition was not detectable between 1 and 3 h. Pertussis toxin (PTx) had no effect on the shear response at any time point. The burst in NO production caused by a change in shear stress appears to be dependent on a PTx-refractory G protein. Sustained shear-mediated production is independent of G protein activation.

Tetrahydrobiopterin synthesis and inducible nitric oxide production in pulmonary artery smooth muscle

1994 ◽  
Vol 266 (4) ◽  
pp. L455-L460 ◽  
Author(s):  
D. K. Nakayama ◽  
D. A. Geller ◽  
M. Di Silvio ◽  
G. Bloomgarden ◽  
P. Davies ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
De Novo ◽  
Interleukin 1 ◽  
No Production ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Pulmonary Artery Smooth Muscle ◽  
Inducible Nitric Oxide

We recently reported (Am. J. Respir. Cell Mol. Biol. 7: 471-476, 1992) that a mixture of lipopolysaccharide (LPS) and cytokines produced a time-dependent increase in mRNA and protein expression of inducible nitric oxide synthase (iNOS) in cultured rat pulmonary artery smooth muscle cells (RPASM). In the current study we extend observations on regulation of iNOS in RPASM by showing that de novo synthesis of tetrahydrobiopterin (BH4) is critical for LPS and cytokine-induced NO production. A mixture of LPS and the cytokines gamma-interferon, interleukin-1 beta, and tumor necrosis factor-alpha increased steady-state levels of mRNA of GTP-cyclohydrolase-I (GTP-CH), the rate-limiting enzyme in BH4 biosynthesis. Levels of mRNA to GTP-CH became detectable by 4 h, with further increases at 24 h by Northern blot analysis and reverse-transcriptase polymerase chain reaction. Total intracellular biopterin levels, undetectable under basal conditions, increased after 24 h exposure to LPS and cytokines (to 32.3 +/- 0.8 pmol/mg protein). LPS and cytokine-induced NO production, determined by nitrite concentrations in the medium, was decreased in a concentration-dependent manner by the GTP-CH inhibitor, 2,4-diamino-6-hydroxypyrimidine (DAHP) at 24 h. DAHP also inhibited completely the LPS- and cytokine-induced accumulation of intracellular biopterins. Sepiapterin, which supplies BH4 through a salvage pathway independent of GTP-CH, reversed the effect of DAHP on LPS and cytokine-induced NO production.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal arginine and protein synthesis are increased during early endotoxemia in mice

2002 ◽  
Vol 282 (2) ◽  
pp. F316-F323 ◽  
Author(s):  
Marcella M. Hallemeesch ◽  
Peter B. Soeters ◽  
Nicolaas E. P. Deutz
Keyword(s):  
Nitric Oxide ◽  
Protein Synthesis ◽  
Protein Metabolism ◽  
De Novo ◽  
Early Response ◽  
No Production ◽  
Arginine Metabolism ◽  
First Time ◽  
Adaptive Role

The kidney has an important function in arginine metabolism, because the kidney is the main endogenous source for de novo arginine production from circulating citrulline. In conditions such as sepsis, nitric oxide (NO) production is increased and is dependent on extracellular arginine availability. To elucidate the adaptive role of renal de novo arginine synthesis in a condition of increased NO production, we studied renal arginine metabolism in a mouse model of endotoxemia. Because arginine flux is largely dependent on protein flux, we also measured protein metabolism in mice. Female mice were injected intraperitoneally with lipopolysaccharide; control mice received 0.9% NaCl. Six hours later, renal blood flow was measured with the use of para-aminohippuric acid. Arginine and protein metabolism were studied using organ-balance, stable-isotope techniques. Systemic NO production was increased in the endotoxin-treated mice. In addition, renal protein synthesis and de novo arginine production from citrulline were increased. However, no effect on renal NO production was observed. In conclusion, increased renal de novo arginine production may serve to sustain systemic NO production. To our knowledge, it was shown for the first time that renal protein synthesis is enhanced in the early response to endotoxemia.

scholarly journals Nitric Oxide Mediates Downregulation of Tissue Factor Expression in Primary Human Pericytes through a p38 MAPK Signaling Pathway

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2425-2425
Author(s):  
Laura Sommerville ◽  
Maureane Hoffman
Keyword(s):  
Nitric Oxide ◽  
Tissue Factor ◽  
P38 Mapk ◽  
Malignant Tumors ◽  
Primary Cultures ◽  
Mapk Signaling ◽  
Signaling Molecules ◽  
No Production ◽  
Dependent Manner ◽  
P38 Inhibitor

Abstract Tissue factor (TF) is a high-affinity receptor for FVII/FVIIa that serves as a key initiator of hemostasis and is thought to also play a functional role in angiogenesis. Elevated TF expression has been linked to upregulated angiogenesis in malignant tumors, while reducing TF expression in experimental tumor models results in decreased angiogenesis. Although these data suggest that high TF expression is critical for angiogenesis, we have reported that TF expression declines significantly in pericytes that surround angiogenic vessels at sites of wound healing. This is the only known example of active TF downregulation, suggesting that pericytes regulate their expression of TF by a unique mechanism. Additionally, TF expression increases in response to many mediators, yet none that decrease TF expression have been described. The goal of this study was to characterize TF downregulation in pericytes and identify mediators of this process. We have previously shown that TF expression in primary cultures of human pericytes is not affected by treatment with various growth factors or inflammatory stimuli, but decreases significantly in response to phorbol 12-myristate 13-acetate (PMA). PMA triggers degradation of TF protein and inhibition of TF mRNA synthesis, both in a Protein Kinase C (PKC)- dependent manner. To identify other signaling molecules in this pathway we used chemical inhibitors to block the activity of signaling molecules downstream of PKC before adding PMA to pericyte cultures. Inhibition of NF-kB, ERK1/2, AKT, JNK, and p38 MAPK did not block degradation of TF protein. However, pericytes that received a p38 inhibitor (SB202190) alone demonstrated significant reduction of TF mRNA. Treatment with SB202190 followed by PMA produced an additive effect on TF mRNA reduction. Western blotting showed that prolonged PMA treatment (>4 hours) produced a sustained decrease in p38 phosphorylation. These data suggest that PMA inhibits p38 activity, and that p38 confers stability to TF mRNA. We have previously found that basic Fibroblast Growth Factor (bFGF) triggers downregulation of pericyte TF a co-culture system with human microvascular endothelial cells. However, transferring bFGF-conditioned endothelial cell media to pericytes cultured alone failed to reproduce TF loss. bFGF has been shown to stimulate nitric oxide (NO) production, and both bFGF and NO have been linked to angiogenesis. This led us to consider NO as a potential labile mediator of TF downregulation. ±6.1%, p<0.01). However, expression of TF mRNA was not reduced at this time, as it is during culture with PMA. Pericytes treated with DETA NO demonstrated sustained p38 phosphorylation for up to 8 hours. Taken together, these data suggest that DETA NO downregulates TF protein but maintains basal levels of TF mRNA, potentially in a p38-dependent manner. Based on these data, we hypothesize that the p38 signaling axis is a key component of a unique pathway of TF regulation in pericytes, and that endothelial nitric oxide contributes to downregulation of pericyte TFin vivo at sites of physiologic angiogenesis. Disclosures Hoffman: Novo Nordisk A/S: Consultancy, Honoraria, Research Funding.

scholarly journals Pin1 as Molecular Switch in Vascular Endothelium: Notes on Its Putative Role in Age-Associated Vascular Diseases

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3287
Author(s):  
Francesca Fagiani ◽  
Marieva Vlachou ◽  
Daniele Di Marino ◽  
Ilaria Canobbio ◽  
Alice Romagnoli ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelium ◽  
Vascular Diseases ◽  
The Elderly ◽  
No Production ◽  
Dependent Manner ◽  
Vascular Homeostasis ◽  
Apoptosis And Inflammation ◽  
Endothelial Nitric Oxide

By controlling the change of the backbones of several cellular substrates, the peptidyl-prolyl cis-trans isomerase Pin1 acts as key fine-tuner and amplifier of multiple signaling pathways, thereby inducing several biological consequences, both in physiological and pathological conditions. Data from the literature indicate a prominent role of Pin1 in the regulating of vascular homeostasis. In this review, we will critically dissect Pin1’s role as conformational switch regulating the homeostasis of vascular endothelium, by specifically modulating nitric oxide (NO) bioavailability. In this regard, Pin1 has been reported to directly control NO production by interacting with bovine endothelial nitric oxide synthase (eNOS) at Ser116-Pro117 (human equivalent is Ser114-Pro115) in a phosphorylation-dependent manner, regulating its catalytic activity, as well as by regulating other intracellular players, such as VEGF and TGF-β, thereby impinging upon NO release. Furthermore, since Pin1 has been found to act as a critical driver of vascular cell proliferation, apoptosis, and inflammation, with implication in many vascular diseases (e.g., diabetes, atherosclerosis, hypertension, and cardiac hypertrophy), evidence indicating that Pin1 may serve a pivotal role in vascular endothelium will be discussed. Understanding the role of Pin1 in vascular homeostasis is crucial in terms of finding a new possible therapeutic player and target in vascular pathologies, including those affecting the elderly (such as small and large vessel diseases and vascular dementia) or those promoting the full expression of neurodegenerative dementing diseases.

Role of cytoskeleton in shear stress-induced endothelial nitric oxide production

1997 ◽  
Vol 273 (1) ◽  
pp. H347-H355 ◽  
Author(s):  
H. L. Knudsen ◽  
J. A. Frangos
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Plasma Membrane ◽  
Cytochalasin D ◽  
Induced Response ◽  
No Production ◽  
Dependent Manner ◽  
Mechanochemical Transduction

To study the role of the cytoskeleton in mechanochemical transduction, human umbilical vein endothelial cells were exposed to cytoskeleton-disrupting or -stabilizing agents, and the flow-induced production of nitric oxide (NO) as monitored by intracellular levels of guanosine 3',5'-cyclic monophosphate (cGMP) was examined. A shear stress of 20 dyn/cm2 elevated cGMP levels approximately twofold relative to basal (stationary) levels (1.9 +/- 0.1 pmol cGMP in stationary controls; P < 0.01). Treatment with 1 microM phalloidin and 0.5 microM cytochalasin D did not significantly affect the flow-induced response (1.77 +/- 0.23 and 2.89 +/- 0.18 pmol cGMP in stationary controls, respectively), whereas disruption of microtubules with 0.5 microM colchicine significantly elevated the response (3.64 +/- 0.18 pmol cGMP in stationary controls; P < 0.01). The NO synthase inhibitor NG-amino-L-arginine abrogated all flow-induced elevations of cGMP, indicating that increased cGMP levels were mediated by NO. Cytoskeletal disruption with 0.2 microM cytochalasin D or 0.5 microM colchicine did not alter cGMP levels in response to 10 nM bradykinin. The role of the plasma membrane in mechanochemical transduction was examined by treatment with cholesteryl hemisuccinate, which attenuated the flow-induced response in a dose-dependent manner. In conclusion, the pathways of flow- and bradykinin-mediated NO production in endothelial cells did not require actin filament turnover or intact actin or microtubule cytoskeletons, and cholesterol, possibly by stiffening the plasma membrane, attenuated the flow response.

Homocysteine thiolactone-induced seizures in adult rats are aggravated by inhibition of inducible nitric oxide synthase

2013 ◽  
Vol 33 (5) ◽  
pp. 496-503 ◽  
Author(s):  
D Hrnčić ◽  
A Rašić-Marković ◽  
D Macut ◽  
V Šušić ◽  
D Djuric ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
No Production ◽  
Dependent Manner ◽  
Latency Time ◽  
Adult Rats ◽  
Homocysteine Thiolactone ◽  
Inos Inhibitor ◽  
Functional Involvement ◽  
Oxide Synthase

Homocysteine and its metabolites (homocysteine thiolactone (HT)) induce seizures via different but still not well-known mechanisms. The role of nitric oxide (NO) in epileptogenesis is highly contradictory and depends on, among other factors, the source of NO production. The aim of the present study was to examine the effects of aminoguanidine, selective inhibitor of inducible NO synthase (iNOS), on HT-induced seizures. Aminoguanidine (50, 75, and 100 mg/kg, intraperitoneally (i.p.)) was injected to rats 30 min prior to inducing HT (5.5 mmol/kg, i.p.). Seizure behavior was assessed by seizure incidence, latency time to first seizure onset, number of seizure episodes, and their severity during observational period of 90 min. Number and duration of spike and wave discharges (SWDs) were determined in electroencephalogram (EEG). Seizure latency time was significantly shortened, while seizure incidence, number, and duration of HT-induced SWD in EEG significantly increased in rats receiving aminoguanidine 100 mg/kg before subconvulsive dose of HT. Aminoguanidine in a dose-dependent manner also significantly increased the number of seizure episodes induced by HT and their severity. It could be concluded that iNOS inhibitor (aminoguanidine) markedly aggravates behavioral and EEG manifestations of HT-induced seizures in rats, showing functional involvement of iNOS in homocysteine convulsive mechanisms.

scholarly journals PPARα agonists regulate lipid metabolism and nitric oxide production and prevent placental overgrowth in term placentas from diabetic rats

2011 ◽  
Vol 47 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Nora Martínez ◽  
Melisa Kurtz ◽  
Evangelina Capobianco ◽  
Romina Higa ◽  
Verónica White ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lipid Metabolism ◽  
Lipid Synthesis ◽  
Diabetic Rats ◽  
Placental Weight ◽  
Peroxidation Of Lipids ◽  
No Production ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Regulate Lipid Metabolism

Maternal diabetes impairs fetoplacental metabolism and growth. Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor capable of regulating lipid metabolism and inflammatory pathways. In this study, we analyzed whether placental and fetal PPARα activation regulates lipid metabolism and nitric oxide (NO) production in term placentas from diabetic rats. Diabetes was induced by neonatal streptozotocin administration. On day 21 of pregnancy, placentas from control and diabetic rats were cultured in the presence of PPARα agonists (clofibrate and leukotriene B4 (LTB4)) for further evaluation of levels, synthesis, and peroxidation of lipids as well as NO production. Besides, on days 19, 20, and 21 of gestation, fetuses were injected with LTB4, and the placentas were explanted on day 21 of gestation for evaluation of placental weight and concentrations of placental lipids, lipoperoxides, and NO metabolites. We found that placentas from diabetic rats showed reduced PPARα concentrations. They presented no lipid overaccumulation but reduced lipid synthesis, parameters negatively regulated by PPARα activators. Lipid peroxidation and NO production, increased in placentas from diabetic rats, were negatively regulated by PPARα activators. Fetal PPARα activation in diabetic rats does not change placental lipid concentrations but reduced placental weight and NO production. In conclusion, PPARα activators regulate lipid metabolism and NO production in term placentas from diabetic rats, an activation that regulates placental growth and can partly be exerted by the developing fetus.

The Signaling Pathways in Nitric Oxide Production by Neutrophils Exposed to N-nitrosodimethylamine

2018 ◽  
Vol 16 (2) ◽  
pp. 194-199
Author(s):  
Wioletta Ratajczak-Wrona ◽  
Ewa Jablonska
Keyword(s):  
Nitric Oxide ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Polymorphonuclear Neutrophils ◽  
Microbial Pathogens ◽  
Human Neutrophils ◽  
No Production ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Background: Polymorphonuclear neutrophils (PMNs) play a crucial role in the innate immune system’s response to microbial pathogens through the release of reactive nitrogen species, including Nitric Oxide (NO). </P><P> Methods: In neutrophils, NO is produced by the inducible Nitric Oxide Synthase (iNOS), which is regulated by various signaling pathways and transcription factors. N-nitrosodimethylamine (NDMA), a potential human carcinogen, affects immune cells. NDMA plays a major part in the growing incidence of cancers. Thanks to the increasing knowledge on the toxicological role of NDMA, the environmental factors that condition the exposure to this compound, especially its precursors- nitrates arouse wide concern. Results: In this article, we present a detailed summary of the molecular mechanisms of NDMA’s effect on the iNOS-dependent NO production in human neutrophils. Conclusion: This research contributes to a more complete understanding of the mechanisms that explain the changes that occur during nonspecific cellular responses to NDMA toxicity.

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