Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.5.1.19 (NOS)
7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of chromaffin cells with nitric oxide (NO) donors (SNP and SNAP) and peroxynitrite produces a time- and dose-dependent necrotic and apoptotic cell death. Necrotic cell death was characterized by both an increase in lactate dehydrogenase and ATP release and changes in nuclei and cell morphology (as seen with fluorescence microscopy analysis with propidium iodide and Hoechst 33342). Apoptotic cell death was characterized by nuclear fragmentation and presence of apoptotic cell bodies, by a decrease in DNA content, and by an increase in DNA fragmentation. Treatment of chromaffin cells with lipopolysaccharide (LPS) or cytokines (interferon-gamma, tumor necrosis factor-alpha) resulted only in apoptotic cell death. Apoptotic effects of NO-inducing compounds were specifically reversed, depending on the stimuli, by the NO scavenger carboxy-PTIO (CPTio) or by the NOS inhibitors L-NMA and thiocitrulline. NO-induced apoptotic death in chromaffin cells was concomitant to a cell cycle arrest in G0G1 phase and a decrease in the number of chromaffin cells in the G2M and S phases of cell cycle. All NO-producing compounds were able to induce activation of caspase 3 and cytochrome c release, and specific inhibitors of caspase 3 and 9, such as Ac-DEVD-CHO (CPP32) and Ac-Z-LEHD-FMK, respectively, prevented NO-induced apoptosis in chromaffin cells. These results suggest that chromaffin cells could be good models for investigating the molecular basis of degeneration in diseases showing death of catecholaminergic neurons, phenomenon in which NO plays an important role.
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PMID:Nitric oxide and peroxynitrite induce cellular death in bovine chromaffin cells: evidence for a mixed necrotic and apoptotic mechanism with caspases activation. 1662 60

Human umbilical vein endothelial cells (HUVEC) from gestational diabetes exhibit reduced adenosine uptake and increased nitric oxide (NO) synthesis. Adenosine transport via human equilibrative nucleoside transporters 1 (hENT1) is reduced by NO by unknown mechanisms in HUVEC. We examined whether gestational diabetes-reduced adenosine transport results from lower hENT1 gene (SLC29A1) expression. HUVEC from gestational diabetes exhibit reduced SLC29A1 promoter activity when transfected with pGL3-hENT1(-2154) compared with pGL3-hENT1(-1114) constructs, an effect blocked by N(G)-nitro-L-arginine methyl ester (L-NAME, NOS inhibitor), but unaltered by S-nitroso-N-acetyl-L,D-penicillamine (SNAP, NO donor). In cells from gestational diabetes transfected with pGL3-hENT1(-2154), L-NAME increased, but SNAP did not alter promoter activity and hENT1 expression. However, in cells from normal pregnancies L-NAME increased, but SNAP reduced promoter activity and hENT1 expression. Adenovirus-silenced eNOS expression increased hENT1 expression and activity in cells from normal or gestational diabetic pregnancies. Thus, reduced adenosine transport may result from downregulation of SLC29A1 expression by NO in HUVEC from gestational diabetes. These findings explain the accumulation of extracellular adenosine detected in cultures of HUVEC from gestational diabetes. In addition, fetal endothelial dysfunction could be involved in the abnormal fetal development and growth seen in gestational diabetes.
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PMID:Nitric oxide reduces adenosine transporter ENT1 gene (SLC29A1) promoter activity in human fetal endothelium from gestational diabetes. 1668 63

Direct renal nitric oxide (NO) measurements were infrequent and no simultaneous measurements of renal cortical and medullary NO and local perfusion. Large-surface NO electrodes were placed in renal cortex and medulla of anaesthetised rats; simultaneously, renal blood flow (RBF, index of cortical perfusion) and medullary laser-Doppler flux (MBF) were determined. NO synthase inhibitors: nonselective (L-NAME) or selective for neuronal NOS (nNOS) (S-methyl-thiocitrulline, SMTC), and NO donor (SNAP), were used to manipulate tissue NO. Baseline tissue NO was significantly higher in medulla (703+/-49 NM) than in cortex (231+/-17 nM). Minimal cortical and medullary NO current measured after maximal L-NAME dose (2.4 mg kg(-1) i.v.) was taken as tissue NO zero kevel. This dose decreased RBF and MBF significantly (-43%). SMTC, 1.2 mg kg(-1) h(-1) i.v., significantly decreased tissue NO by 105+/-32 nM in cortex and 546+/-64 nM in medulla, RBF and MBF decreased 30% and 20%, respectively. Renal artery infusion of SNAP, 0.24 mg kg(-1) min(-1) significantly increased tissue NO by 139+/-18 nM in cortex and 948+/-110 nM in medulla. Since inhibition of nNOS decreased medullary NO by 80% and MBF by 20% only, this isoform has probably minor role in the maintenance of medullary perfusion.
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PMID:Renal tissue NO and intrarenal haemodynamics during experimental variations of NO content in anaesthetised rats. 1744 Feb 33

Inflammatory and infectious conditions were simulated in cultures of ras/myc-transformed serum-free mouse embryo (ras/myc SFME) cells, using interferon-gamma (IFN-gamma, 100 units/ml) and lipopolysaccharide (LPS, 0.5 microg/ml) co-treatment for 24 h, to investigate their effects on the expression of inducible nitric oxide synthase (iNOS) mRNA and the production of NO. Aminoguanidine (AG, 1 mM; an NOS inhibitor) along with IFN-gamma and LPS, S-nitroso-N-acetyl-DL-penicillamine (SNAP, 100 microM; an NO donor) and/or (+/-)-N-[(E)-4-Ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexene-1-yl]-3-pyridine carboxamide (NOR4, 100 microM; an NO donor), were also added to analyze the possible association of NO with matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Co-treatment of cells with IFN-gamma and LPS increased iNOS mRNA expression, NO production, MMP-9 mRNA expression, and 105 kDa MMP-9 production. Additional treatment with the NOS inhibitor AG inhibited NO production, but did not down-regulate the expression of MMP-9 mRNA or 105 kDa MMP-9. The NO donors SNAP and NOR4 did not affect the expression of MMP-9 mRNA, 105 kDa MMP-9 or TIMP-1 mRNA. These results suggest that ras/myc SFME cells respond to infectious and inflammatory conditions and can enhance malignancy as cancer cells due to their increased levels of NO and MMP-9 production, but that NO is not directly associated with MMP-9 in these cells.
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PMID:Ras/myc-transformed serum-free mouse embryo cells under simulated inflammatory and infectious conditions increase levels of nitric oxide and matrix metalloproteinase-9 without a direct association between them. 1766 Sep 54

Nitric oxide (NO) and 5'-AMP-activated protein kinase (AMPK) are involved in glucose transport and mitochondrial biogenesis in skeletal muscle. Here, we examined whether NO regulates the expression of the major glucose transporter in muscle (GLUT4) and whether it influences AMPK-induced upregulation of GLUT4. At low levels, the NO donor S-nitroso-N-penicillamine (SNAP, 1 and 10 microM) significantly increased GLUT4 mRNA ( approximately 3-fold; P < 0.05) in L6 myotubes, and cotreatment with the AMPK inhibitor compound C ablated this effect. The cGMP analog 8-bromo-cGMP (8-Br-cGMP, 2 mM) increased GLUT4 mRNA by approximately 50% (P < 0.05). GLUT4 protein expression was elevated 40% by 2 days treatment with 8-Br-cGMP, whereas 6 days treatment with 10 microM SNAP increased GLUT4 expression by 65%. Cotreatment of cultures with the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one prevented the SNAP-induced increase in GLUT4 protein. SNAP (10 microM) also induced significant phosphorylation of alpha-AMPK and acetyl-CoA carboxylase and translocation of phosphorylated alpha-AMPK to the nucleus. Furthermore, L6 myotubes exposed to 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) for 16 h presented an approximately ninefold increase in GLUT4 mRNA, whereas cotreatment with the non-isoform-specific NOS inhibitor N(G)-nitro-l-arginine methyl ester, prevented approximately 70% of this effect. In vivo, GLUT4 mRNA was increased 1.8-fold in the rat plantaris muscle 12 h after AICAR injection, and this induction was reduced by approximately 50% in animals cotreated with the neuronal and inducible nitric oxide synthases selective inhibitor 1-(2-trifluoromethyl-phenyl)-imidazole. We conclude that, in skeletal muscle, NO increases GLUT4 expression via a cGMP- and AMPK-dependent mechanism. The data are consistent with a role for NO in the regulation of AMPK, possibly via control of cellular activity of AMPK kinases and/or AMPK phosphatases.
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PMID:Nitric oxide increases GLUT4 expression and regulates AMPK signaling in skeletal muscle. 1766 90

Sepsis causes changes in vascular resistance and hypovolemia. Previous studies have demonstrated that the spleen regulates blood volume via atrial natiuretic peptide (ANP). We hypothesized that LPS alters extrasplenic responses to ANP via endothelial-dependent mechanisms and studied the role of NO and endothelin 1 (ET-1). Isolated extrasplenic arteries and veins (vessels in mesentery adjoining spleen) were obtained from male Wistar rats weighing 200 to 280 g (n = 102) and mounted on a pressure myograph to determine intraluminal diameter for 4 h. Isolated vessels constricted in response to the half-maximum response of ANP (veins, 30% +/- 1.7%; arteries, 34.5 +/- 1.7%; P < 0.05), and this was abolished by the NO donor S-nitroso-N-acetylpenicillamine (SNAP 75 microM). Arteries and veins incubated with LPS (50 microg mL(-1) for 4 h) were unresponsive to ANP, and constriction was not restored by the NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME 100 microM). However, venular constriction returned in the presence of the ET-1 antagonist Bosentan, increasing from -1.5 +/- 1.2 (10 min) to -10 +/- 2.5% (4 h) with LPS + Bosentan (3 x 10(-6) M) compared with -2.3 +/- 1.2 and 0% with LPS alone. In conclusion, LPS abolished endothelial-dependent extrasplenic venular constriction to ANP partially due to increased ET-1, whereas NO seemed to modulate vascular responses to ANP.
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PMID:LPS abolishes extrasplenic vasoconstriction to atrial natriuretic peptide: the role of NO and endothelin 1. 1788 45

Lysophosphatidylcholine (LPC) accumulates in the ischaemic myocardium and is arrhythmogenic. We have examined the mechanisms underlying the effects of LPC on the late cardiac Na(+) current (I(L)Na). Na(+) currents were recorded in HEK293 cells expressing Na(V)1.5 and isolated rat ventricular myocytes. LPC enhanced recombinant I(L)Na, while it reduced peak Na(+) current. Computer modeling of human ventricular myocyte action potentials predicted a marked duration prolonging effect and arrhythmogenic potential due to these effects of LPC on peak and late currents. Enhancement of recombinant I(L)Na was suppressed by the antioxidant ascorbic acid and by the NADPH oxidase inhibitor DPI. Inhibitors of the mitochondrial electron transport chain (rotenone, TTFA and myxothiazol) were without effect on LPC responses. The superoxide donor pyrogallol was without effect on I(L)Na. Enhancement of I(L)Na was abrogated by the NOS inhibitors l-NAME and 7-nitroindazole, while LPC induced an l-NAME-sensitive production of NO, measured as enhanced DAF-FM fluorescence, in both HEK293 cells and ventricular myocytes. Despite this, the NO donors SNAP and SNP caused no change in I(L)Na. However, SNAP enhanced TTX-sensitive recombinant and native I(L)Na in the presence of pyrogallol, suggesting peroxynitrite formation as a mediator of the response to LPC. In support of this, the peroxynitrite scavenger FeTPPS prevented the response of I(L)Na to LPC. Peroxynitrite formation provides a novel mechanism by which LPC regulates the late cardiac Na(+) current.
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PMID:Peroxynitrite formation mediates LPC-induced augmentation of cardiac late sodium currents. 1820 18

In locusts, a central pattern generator underlies the rhythmic movements of the ovipositor valves that serve to drive the abdomen into damp soil in order to lay eggs. We have investigated the role of nitric oxide (NO) in the control of this oviposition digging rhythm. NO increases the frequency of the rhythm by acting via sGC to elevate cGMP, which in turn acts via PKG. Increasing exogenous NO levels using the NO donors SNAP and PAPANONOate increased the cycle frequency of the fictive digging rhythm, as did increasing endogenous NO by bath application of the substrate for NOS, l-arginine. On the other hand, application of the NO scavenger PTIO decreased the cycle frequency, indicating that NO must normally exert a continuous and dynamic role on the central pattern generator underlying the oviposition rhythm. Inhibiting the main molecular target of NO, soluble guanylate cyclase, with ODQ reduced the cycle frequency of the rhythm, suggesting that NO mediated its effects via sGC and cyclic GMP. Further evidence for this was produced by bath application of 8-Br-cGMP, which increased the frequency of the rhythm. Bath application of the generic protein kinase inhibitor and a selective PKG inhibitor, H-7 and KT-5823, respectively, reduced the frequency of the rhythm, suggesting that PKG acted as a target for cGMP. Thus, we conclude that NO plays a key role in regulating the frequency of the central pattern generator controlling rhythmic egg-laying movements in locusts by acting via sGC/cGMP-PKG.
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PMID:Nitrergic modulation of an oviposition digging rhythm in locusts. 1805 33

High D-glucose reduces human equilibrative nucleoside transporter 1 (hENT1)-mediated adenosine uptake involving endothelial nitric oxide synthase (eNOS), mitogen-activated protein (MAP) kinase kinases 1 and 2/MAP kinases p42/44 (MEK/ERKs), and protein kinase C (PKC) activation in human umbilical vein endothelium (HUVEC). Since NO represses SLC29A1 gene (hENT1) promoter activity we studied whether D-glucose-reduced hENT1-adenosine transport results from lower SLC29A1 expression in HUVEC primary cultures. HUVEC incubation (24 h) with high D-glucose (25 mM) reduced hENT1-adenosine transport and pGL3-hENT1(-1114) construct SLC29A1 reporter activity compared with normal D-glucose (5 mM). High D-glucose also reduced pGL3-hENT1(-1114) reporter activity compared with cells transfected with pGL3-hENT1(-795) construct. N(G)-nitro-L-arginine methyl ester (L-NAME, NOS inhibitor), PD-98059 (MEK1/2 inhibitor), and/or calphostin C (PKC inhibitor) blocked D-glucose effects. Insulin (1 nM) and phorbol 12-myristate 13-acetate (PMA, 100 nM, PKC activator), but not 4alpha-phorbol 12,13-didecanoate (4alphaPDD, 100 nM, PMA less active analogue) reduced hENT1-adenosine transport. L-NAME and PD-98059 blocked insulin effects. L-NAME, PD-98059, and calphostin C increased hENT1 expression without altering protein or mRNA stability. High D-glucose increased Sp1 transcription factor protein abundance and binding to SLC29A1 promoter, phenomena blocked by L-NAME, PD-98059, and calphostin C. Sp1 overexpression reduced SLC29A1 promoter activity in normal D-glucose, an effect reversed by L-NAME and further reduced by S-nitroso-N-acetyl-L,D-penicillamine (SNAP, NO donor) in high D-glucose. Thus, reduced hENT1-mediated adenosine transport in high D-glucose may result from increased Sp1 binding to SLC29A1 promoter down-regulating hENT1 expression. This phenomenon depends on eNOS, MEK/ERKs, and PKC activity, suggesting potential roles for these molecules in hyperglycemia-associated endothelial dysfunction.
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PMID:High D-glucose reduces SLC29A1 promoter activity and adenosine transport involving specific protein 1 in human umbilical vein endothelium. 1806 6

The mechanisms of NO inhibition of CaMK [Ca(2+)/CaM (calmodulin)-dependent protein kinase] II activity were studied. In rat pituitary tumour GH3 cells, TRH [thyrotrophin (TSH)-releasing hormone]-stimulated phosphorylation of nNOS [neuronal NOS (NO synthase)] at Ser(847) was sensitive to an inhibitor of CaMKs, KN-93, and was enhanced by inhibition of nNOS with 7NI (7-nitroindazole). Enzyme activity of CaMKII following in situ treatment with 7NI was also increased. The in vitro activity of CaMKII was inhibited by co-incubation either with nNOS and L-arginine or with NO donors SNAP (S-nitroso-N-acetyl-DL-penicillamine) and DEA-NONOate [diethylamine-NONOate (diazeniumdiolate)]. Once inhibited by these treatments, CaMKII was observed to undergo full reactivation on the addition of a reducing reagent, DTT (dithiothreitol). In transfected cells expressing CaMKII and nNOS, treatment with the calcium ionophore A23187 further revealed nNOS phosphorylation at Ser(847), which was enhanced by 7NI and CaMKII S-nitrosylation. Mutated CaMKII (C6A), in which Cys(6) was substituted with an alanine residue, was refractory to 7NI-induced enhancement of nNOS phosphorylation or to CaMKII S-nitrosylation. Furthermore, we could identify Cys(6) as a direct target for S-nitrosylation of CaMKII using MS. In addition, treatment with glutamate caused an increase in CaMKII S-nitrosylation in rat hippocampal slices. This glutamate-induced S-nitrosylation was blocked by 7NI. These results suggest that inactivation of CaMKII mediated by S-nitrosylation at Cys(6) may contribute to NO-induced neurotoxicity in the brain.
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PMID:Nitric oxide-mediated modulation of calcium/calmodulin-dependent protein kinase II. 1827 54


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