Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.13.39 (NO synthase)
 15,778 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the heart, in situ local myocardial blood flow (MBF) varies greater than 10-fold between individual areas and displays a spatially heterogeneous pattern. To analyze its molecular basis, we analyzed protein expression of low and high flow samples (300 mg, <50% or >150% of mean MBF, each n=30) of six beagle dogs by 2-D polyacrylamide gel electrophoresis (380 +/- 78 spots/gel). In low flow samples, dimethylarginine dimethylaminohydrolase (DDAH1) was increased greatly (+377%, compared with high flow samples). This increase resulted in a 75% reduction of asymmetric dimethylarginine (ADMA), the potent endogenous inhibitor of NO synthase, whereas eNOS showed no difference. Low flow samples exhibited enhanced expression of GAPDH (+89%) and phosphoglycerate kinase (+100%), whereas hydroxyacyl-CoA dehydrogenase, electron transfer flavoprotein, myoglobin, and desmin were decreased. Assessing local MBF on different days within 2 weeks revealed a high degree of MBF stability (r2 > 0.79). Thus, stable differences in local MBF are associated with significant differences in local gene and protein expression. In low flow areas, the increased DDAH1 reduces ADMA concentration and NOS inhibition, which strongly suggests enhanced NO formation. Low flow areas are also characterized by a higher glycolytic and a lower fatty acid oxidation capacity. Both the shift in substrate utilization and the rise in NO may contribute to the known lower oxygen consumption in these areas.
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PMID:Myocardial proteome analysis reveals reduced NOS inhibition and enhanced glycolytic capacity in areas of low local blood flow. 1191 76

Nitric oxide (NO) is a potent mediator synthesized by a variety of cells involved in inflammatory reactions. We investigated the expression of NO synthase (NOS) in rat peritoneal mast cells (PMC). Small amounts of eNOS mRNA were detected basally, whereas neither mRNA for iNOS nor nNOS was detected in unstimulated PMC. Following stimulation by antigen, interferon-gamma (IFN-gamma), or anti-CD8 antibody, PMC up-regulated iNOS mRNA expression. In situ RT-PCR confirmed that iNOS mRNA originated from PMC. Production of iNOS protein was confirmed in stimulated PMC by immunohistochemistry. Upon stimulation with antigen, IFN-gamma, or anti-CD8, nitrite production was increased significantly (8.4+/-0.6, 7.6+/-0.9, and 6.6+/-0.9 microM/2x10(5) cells/48 h NO2-, respectively; P<0.01), whereas unstimulated PMC released 2.1 +/- 0.3 microM/2 x 10(5) cells/48 h NO2-. These findings demonstrate that in vivo-derived PMC transcribe and translate mRNA for NOS and produce NO.
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PMID:Nitric oxide synthase and nitric oxide production in in vivo-derived mast cells. 1192 48

Nitric oxide (NO) produced by NO synthase (NOS) serves as a ubiquitous mediator molecule involved in many physiologic lung functions, including regulation of vascular and bronchial tone, immunocompetence, and neuronal signaling. On the other hand, excessive and inappropriate NO synthesis in inflammation and sepsis has been implicated in vascular abnormalities and cell injury. At least three different NOS isoforms (neuronal/brain [bNOS], inducible [iNOS], and endothelial [eNOS]) have been described, which are all expressed in normal lung tissue. We investigated the cell-specific expression of bNOS, iNOS, and eNOS in perfused control rat lungs and lungs undergoing stimulation with endotoxin in the presence and absence of plasma constituents. Lung immunohistochemistry and quantitative evaluation of staining intensity showed endotoxin-induced increase in iNOS expression in particular in bronchial epithelial cells, cells of the bronchus-associated lymphoid tissue (BALT), alveolar macrophages, and vascular smooth muscle cells in a time- and dose-dependent fashion. In endothelial cells, which did not express iNOS at baseline, newly induced iNOS was found in response to endotoxin. In contrast, expression of eNOS was markedly suppressed under endotoxin challenge, particularly in bronchial epithelium, BALT, and alveolar macrophages but also in vascular smooth muscle cells and endothelial cells. eNOS expression in bronchial smooth muscle cells was not altered. In contrast to iNOS and eNOS, cellular expression of bNOS in epithelial cells, nerve fibers, BALT, and endothelial cells did not change in response to endotoxin. All changes in NOS regulation were found to be independent of plasma constituents. We conclude that endotoxin exerts a profound impact on the cell-specific NOS regulation in a large number of lung cell types. Prominent features include de novo synthesis or up-regulation of iNOS, in contrast to down-regulation of eNOS, which may well contribute to vascular abnormalities, inflammatory sequelae, and loss of physiologic functions in septic lung failure.
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PMID:Cell-specific nitric oxide synthase-isoenzyme expression and regulation in response to endotoxin in intact rat lungs. 1195 Sep

Many individuals with cardiovascular diseases undergo periodic exercise conditioning with or with out medication. Therefore, this study investigated the interaction of exercise training and chronic nitric oxide synthase (NOS) inhibitor (Nitro-L-Arginine Methyl Ester, L-NAME) treatment on blood pressure and its correlation with aortic nitric oxide (NO), antioxidant defense system and oxidative stress parameters in rats. Fisher 344 rats were divided into four groups: (1) sedentary control, (2) exercise training (ET) for 8 weeks, (3) L-NAME (10 mg/kg, subcutaneous for 8 weeks) and (4) ET + L-NAME. Blood pressure (BP) was monitored weekly for 8 weeks with tail-cuff method. The animals were sacrificed 24 h after last treatments and thoracic aortic rings were isolated and analyzed. Exercise conditioning resulted in a significant increase in respiratory exchange ratio (RER), aortic NO production, NO synthase activity and inducible iNOS protein expression. Training significantly enhanced aortic GSH levels, GSH/GSSG ratio and up-regulation of aortic CuZn-SOD, Mn-SOD, catalase (CAT), glutathione peroxidase (GSH-Px) activity and protein expression and significantly decreased aortic lipid peroxidation. Chronic L-NAME administration resulted in a significant depletion of aortic NO, NOS activity, endothelial (eNOS) and iNOS protein expression, GSH level, GSH/GSSG ratio, down-regulation of aortic antioxidant enzyme activities and protein expressions. Aortic xanthine oxidase (XO) activity significantly increased with increased lipid peroxidation and protein oxidation after L-NAME administration. The biochemical changes were accompanied by increased in BP. Interaction of training and chronic NOS inhibitor treatment resulted in normalization of BP and aortic antioxidant enzyme activity and protein expression, up-regulation of aortic GSH/GSSG ratio, NO levels, Mn-SOD protein expression, depletion of GSSG, protein oxidation and lipid peroxidation. The data suggest that training attenuated the oxidative injury caused by chronic NOS inhibitor treatment by up-regulating the NO and antioxidant systems and lowering the BP in rats.
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PMID:Exercise conditioning attenuates the hypertensive effects of nitric oxide synthase inhibitor in rat. 1195 54

Estrogen has important atheroprotective and vasoactive properties related to its capacity to stimulate nitric oxide (NO) production by endothelial NO synthase. Previous work has shown that these effects are mediated by estrogen receptor (ER) alpha functioning in a nongenomic manner via calcium-dependent, MAP kinase-dependent mechanisms. Recent studies have demonstrated that estradiol (E(2)) activates eNOS in isolated endothelial plasma membranes in the absence of added calcium, calmodulin or eNOS cofactors. Studies of blockade by ICI 182,780 and by ER alpha antibody, and also immunoidentification experiments indicate that the process is mediated by a subpopulation of plasma membrane-associated ER alpha. Fractionation of endothelial cell plasma membranes has further revealed that ER alpha protein is localized to caveolae, and that E(2) causes stimulation of eNOS in isolated caveolae which is ER-dependent and calcium-dependent, whereas noncaveolae membranes are insensitive. Furthermore, in intact endothelial cells the activation of eNOS by E(2) is prevented by pertussis toxin, and exogenous GDP beta S inhibits the response in isolated plasma membranes. Coimmunoprecipitation studies have shown that E(2) exposure causes interaction between ER alpha and G(alpha i) on the plasma membrane, and eNOS activation by E(2) is enhanced by overexpression of G(alpha i) and attenuated by expression of a protein regulator of G protein signaling (RGS), RGS4. Thus, a subpopulation of ER alpha is localized to caveolae in endothelial cells, where they are coupled via G(alpha i) to eNOS in a functional signaling module. Emphasizing the dependence on cell surface-associated receptors, these observations provide evidence for the existence of a steroid receptor fast-action complex, or SRFC, in caveolae.
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PMID:Rapid activation of endothelial NO synthase by estrogen: evidence for a steroid receptor fast-action complex (SRFC) in caveolae. 1196 Jun 16

all-trans-Retinoic acid (atRA) has important effects on the developing and mature cardiovascular system. Nitric oxide (NO) production has been associated with the atRA-induced differentiation of neuronal cells, and we hypothesized that NO may also mediate certain actions of atRA in the cardiovascular system. We studied the effects of atRA on NO production by endothelial cells and determined whether regulation of enzymes responsible for metabolism of asymmetric dimethylarginine (ADMA) contributed to the effects seen. Murine endothelioma (sEnd.1) cells were incubated with or without atRA. Nitrite production was determined using the Griess reaction. The expression of NO synthase (NOS) and dimethylarginine dimethylaminohydrolase (DDAH) genes was determined by Northern blotting. A reporter gene assay was also used to study the effect of atRA on the DDAH II promoter. atRA significantly increased nitrite production by sEnd.1 cells despite no increase in eNOS expression. atRA also increased DDAH II gene expression and promoter activity and reduced the ratio of ADMA to symmetric dimethylarginine (SDMA) in culture medium. The DDAH inhibitor 4124W significantly reduced the induction of NO synthesis by atRA. The present study demonstrates that atRA increases NO synthesis in endothelial cells without increasing eNOS expression. atRA also increases the expression of DDAH II, the predominant DDAH isoform in endothelial cells. Our data suggests that the induction of NO synthesis by atRA may be facilitated by DDAH II. This pathway may help to explain some of the effects of atRA on the cardiovascular system.
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PMID:all-trans-Retinoic acid increases nitric oxide synthesis by endothelial cells: a role for the induction of dimethylarginine dimethylaminohydrolase. 1196 68

We aimed to elucidate the possible role of phenotypic alterations and oxidative stress in age-related endothelial dysfunction of coronary arterioles. Arterioles were isolated from the hearts of young adult (Y, 14 weeks) and aged (A, 80 weeks) male Sprague-Dawley rats. For videomicroscopy, pressure-induced tone of Y and A arterioles and their passive diameter did not differ significantly. In A, arterioles L-NAME (a NO synthase blocker)-sensitive flow-induced dilations were significantly impaired (Y: 41+/-8% versus A: 3+/-2%), which could be augmented by superoxide dismutase (SOD) or Tiron (but not L-arginine or the TXA(2) receptor antagonist SQ29,548). For lucigenin chemiluminescence, O(2)(.-) generation was significantly greater in A than Y vessels and could be inhibited with SOD and diphenyliodonium. NADH-driven O(2)(.-) generation was also greater in A vessels. Both endothelial and smooth muscle cells of A vessels produced O(2)(.-) (shown with ethidium bromide fluorescence). For Western blotting, expression of eNOS and COX-1 was decreased in A compared with Y arterioles, whereas expressions of COX-2, Cu/Zn-SOD, Mn-SOD, xanthine oxidase, and the NAD(P)H oxidase subunits p47(phox), p67(phox), Mox-1, and p22(phox) did not differ. Aged arterioles showed an increased expression of iNOS, confined to the endothelium. Decreased eNOS mRNA and increased iNOS mRNA expression in A vessels was shown by quantitative RT-PCR. In vivo formation of peroxynitrite was evidenced by Western blotting, and immunohistochemistry showing increased 3-nitrotyrosine content in A vessels. Thus, aging induces changes in the phenotype of coronary arterioles that could contribute to the development of oxidative stress, which impairs NO-mediated dilations.
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PMID:Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. 1206 18

The onset of tissue ischemia is associated with significant changes in the expression of heparan sulfate- (HS) carrying core proteins that, in turn, lead to alterations in composition of the extracellular HS matrix. Since HS can bind numerous growth factors and cytokines, such changes in the HS matrix content can have profound effects on the ability of these factors to interact with their target cells. To investigate the role of increased HS matrix content on microvascular function, we used alpha-myosin heavy chain (MHC) promoter to overexpress a HS-carrying core protein, syndecan-4, in cardiac myocytes in mice. Mice expressing the transgene (alpha MHC-S4) demonstrated a significant increase in nitric oxide (NO) release in the coronary effluent in response to fibroblast growth factor 2 (FGF2, 1 microg/mL) administration despite similar expression levels of NO synthase genes II and III (iNOS and eNOS, respectively). In vitro studies of coronary microvessels derived from alpha MHC-S4 mice demonstrated increased relaxation response to FGF2 compared to control mice. At the same time, vasodilator response to adenosine diphosphate (ADP) was significantly impaired in alpha MHC-S4 mice-derived microvessels. Addition of exogenous HS to microvessels derived from control mice enhanced FGF2-induced vasodilation while inhibiting ADP-induced vasomotion. The vasomotor activity of the endothelial receptor-independent agent (A23187) and the endothelium-independent agent (sodium nitroprusside) was not affected by heparan sulfate. These results demonstrate that alterations in HS production have a profound and heterogeneous effect on endothelial receptor-dependent vasodilators and point to a novel role of the HS matrix in regulation of microvascular homeostasis.
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PMID:Modulation of microvascular signaling by heparan sulfate matrix: studies in syndecan-4 transgenic mice. 1207 29

Previously, we showed that increased extracellular tonicity promotes increased type A natriuretic peptide receptor (NPR-A) expression through a p38 MAPKbeta pathway in inner medullary collecting duct cells. The endothelial and inducible nitric-oxide synthase (eNOS and iNOS respectively) genes are also expressed in this nephron segment and are thought to play a role in regulating urinary sodium concentration. We sought to determine whether changes in tonicity might regulate NOS gene expression, and if so, whether these latter changes might be linked mechanistically to the increase in NPR-A gene expression. Increased extracellular tonicity effected a time-dependent reduction in eNOS and iNOS protein levels, eNOS mRNA levels, and eNOS gene promoter activity over the first 8 h of the incubation. Although levels of the eNOS mRNA and promoter activity had returned to normal after 24 h, eNOS protein levels remained low at 24-36 h, and recovery was not complete even at 48 h. The decrease in eNOS expression was signaled in large part through a p38 MAPK-dependent mechanism. Reduction in eNOS expression together with the concomitant decline in intracellular cyclic GMP levels appears to account for a significant portion of the p38 MAPK-dependent osmotic stimulation of NPR-A gene expression noted previously. Collectively, these findings support the existence of a complex regulatory circuitry in the cells of the inner medullary collecting duct linking two independent cyclic GMP-generating signal transduction systems involved in regulation of urinary sodium concentration.
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PMID:Osmoregulation of endothelial nitric-oxide synthase gene expression in inner medullary collecting duct cells. Role in activation of the type A natriuretic peptide receptor. 1208 97

The effect of transient uteroplacental ischemia on nitric oxide (NO) levels, enzymatic activity, and expression of NO synthase (NOS) isoforms was studied in fetal rat brains. Fetuses were subjected to ischemia by clamping the uterine arteries for 5 min on gestational day 17 (GD17). At different times after ischemia, fetuses were delivered by Cesarean section under anesthesia to obtain the brains. Transient uteroplacental ischemia produced a time dependent increase in nitrite levels in the brain, reaching a maximum value (300 +/- 25% of baseline) 24 h after uterine artery occlusion and remaining elevated as long as 48 h. Significantly increased nitrite levels were found in the cerebral cortex but not in the mesencephalon and cerebellum. The ischemia-induced increment in nitrite levels was totally blocked by either L-NAME (10 mg/kg) or AMT (0.65 mg/kg) administered i.p. 1 h before uterine artery occlusion. Both Ca(2+)-dependent and Ca(2+)-independent NOS activities in the cerebral cortex remained significantly increased with respect to controls after 24 h following the ischemia. Reverse transcriptase-polymerase chain reaction showed augmented levels of mRNAs for both nNOS and iNOS when compared with controls at 8 h after ischemia. At 36 h, nNOS mRNA returned to basal levels whereas eNOS mRNA levels increased and iNOS mRNA remained elevated. Our results show that the three NOS isoforms participate in increasing NO levels after transient ischemia and suggest a biphasic and differential regulation of the expression of constitutive NOS isoforms in the rat cerebral cortex.
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PMID:Nitric oxide and nitric oxide synthases in the fetal cerebral cortex of rats following transient uteroplacental ischemia. 1211 58


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