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)

In experimental hypercholesterolemia, endothelium-dependent relaxations decrease, as does endothelial immunoreactivity for nitric oxide (NO) synthase (NOS; eNOS) in coronary arteries. Systemic levels of NO also decrease with concomitant elevations in systemic circulating levels of endothelin (ET)-1. Chronic treatment of hypercholesterolemic pigs with ET-receptor antagonists increases circulating NO and improves endothelium-dependent relaxations. Mechanisms causing these increases are not known. Therefore, experiments were designed to test the hypothesis that chronic administration of ET-receptor antagonists to hypercholesterolemic pigs increases NO production through increases in NOS activity. Female juvenile pigs were fed a 2% cholesterol atherogenic diet and were randomly allocated to receive no treatment (controls), a selective ET(A)-receptor antagonist (ABT-624), or a combined ET(A) + ET(B)-receptor antagonist (RO-48-5695) daily for 12 wk. After 12 wk, endothelial cells from thoracic aorta were prepared for measurement of eNOS mRNA or eNOS activity. Total cholesterol, low-density-lipoprotein cholesterol, and concentrations of ET-1 were significantly higher in all three groups at 12 wk compared with baseline levels. Circulating plasma-oxidized products of NO (NOx) increased with ET-receptor blockade. NOS mRNA was similar among groups. Total and Ca-dependent NOS activity was significantly higher in aortic endothelial cells from the ET(A) + ET(B)-treated pigs compared with those treated with ET(A) antagonist alone. These results suggest that changes in systemic NOx after chronic inhibition of ET(A) + ET(B) receptors in hypercholesterolemia may result from posttranscriptional changes in NOS.
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PMID:Treatment with endothelin-receptor antagonists increases NOS activity in hypercholesterolemia. 1118 88

We have done consecutive studies to investigate the effects of impaired lipid metabolism on the contractile and relaxation response of cavernous smooth muscles and to elucidate its pathogenesis: 1) incidence of hyperlipidemia in impotent patients; 2) erection response to intracavernous injection of papaverine in impotent patients with hyperlipidemia; 3) relaxation responses of isolated cavernosal smooth muscles to endothelium-independent and endothelium-dependent vasodilators in impotent patients with hypercholesterolemia or hypertriglyceridemia; 4) involvement of superoxide radical in the impaired endothelium-dependent relaxation of cavernous smooth muscle in hypercholesterolemic rabbits; 5) effects of isolated lipoproteins and triglyceride, combined oxidized LDL plus triglyceride, and combined oxidized LDL plus HDL on contractile and relaxation response of rabbit cavernous smooth muscles; 6) involvement of e-NOS in the impaired endothelium-dependent relaxation of cavernous smooth muscle in hypercholesterolemic rabbit. Hypercholesterolemia may cause impairment of endothelium-dependent relaxation. Oxidized LDL is the major causative cholesterol of the impaired relaxation response. A chain reaction, the production of superoxide radicals and functional impairment of eNOS may be a major cause of the functional impairment in the early stages of hypercholesterolemia.
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PMID:Hyperlipidemia and erectile dysfunction. 1122 73

We examined whether overproduction of endogenous nitric oxide (NO) can prevent hypoxia-induced pulmonary hypertension and vascular remodeling by using endothelial NO-overexpressing (eNOS-Tg) mice. Male eNOS-Tg mice and their littermates (wild-type, WT) were maintained in normoxic or 10% hypoxic condition for 3 weeks. In normoxia, eNOS protein levels, Ca(2+)-dependent NOS activity, and cGMP levels in the lung of eNOS-Tg mice were higher than those of WT mice. Activity of eNOS and cGMP production in the lung did not change significantly by hypoxic exposure in either genotype. Chronic hypoxia did not induce iNOS expression nor increase its activity in either genotype. Plasma and lung endothelin-1 levels were increased by chronic hypoxia, but these levels were not significantly different between the 2 genotypes. In hemodynamic analysis, right ventricular systolic pressure (RVSP) in eNOS-Tg mice was similar to that in WT mice in normoxia. Chronic hypoxia increased RVSP and induced right ventricular hypertrophy in both genotypes; however, the degrees of these increases were significantly smaller in eNOS-Tg mice. Histological examination revealed that hypoxic mice showed medial wall thickening in pulmonary arteries. However, the increase of the wall thickening in small arteries (diameter <80 microm) by chronic hypoxia was inhibited in eNOS-Tg mice. Furthermore, muscularization of small arterioles was significantly attenuated in eNOS-Tg mice. Thus, we demonstrated directly that overproduction of eNOS-derived NO can inhibit not only the increase in RVSP associated with pulmonary hypertension but also remodeling of the pulmonary vasculature and right ventricular hypertrophy induced by chronic hypoxia.
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PMID:Reduced hypoxic pulmonary vascular remodeling by nitric oxide from the endothelium. 1123 Feb 92

To clarify the role of the autoinhibitory insert in the endothelial (eNOS) and neuronal (nNOS) nitric-oxide synthases, the insert was excised from nNOS and chimeras with its reductase domain; the eNOS and nNOS inserts were swapped and put into the normally insertless inducible (iNOS) isoform and chimeras with the iNOS reductase domain; and an RRKRK sequence in the insert suggested by earlier peptide studies to be important (Salerno, J. C., Harris, D. E., Irizarry, K., Patel, B., Morales, A. J., Smith, S. M., Martasek, P., Roman, L. J., Masters, B. S., Jones, C. L., Weissman, B. A., Lane, P., Liu, Q., and Gross, S. S. (1997) J. Biol. Chem. 272, 29769-29777) was mutated. Insertless nNOS required calmodulin (CaM) for normal NOS activity, but the Ca(2+) requirement for this activity was relaxed. Furthermore, insert deletion enhanced CaM-free electron transfer within nNOS and chimeras with the nNOS reductase, emphasizing the involvement of the insert in modulating electron transfer. Swapping the nNOS and eNOS inserts gave proteins with normal NOS activities, and the nNOS insert acted normally in raising the Ca(2+) dependence when placed in eNOS. Insertion of the eNOS insert into iNOS and chimeras with the iNOS reductase domain significantly lowered NOS activity, consistent with inhibition of electron transfer by the insert. Mutation of the eNOS RRKRK to an AAAAA sequence did not alter the eNOS Ca(2+) dependence but marginally inhibited electron transfer. The salt dependence suggests that the insert modulates electron transfer within the reductase domain prior to the heme/reductase interface. The results clarify the role of the reductase insert in modulating the Ca(2+) requirement, electron transfer rate, and overall activity of nNOS and eNOS.
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PMID:Control of electron transfer in nitric-oxide synthases. Swapping of autoinhibitory elements among nitric-oxide synthase isoforms. 1126 92

Evidence suggests that vascular and inflammatory components may be important in the aetiology of dementia and genetic risk factors affecting these processes may therefore influence disease development. Recently, polymorphisms in the endothelial constitutive nitric oxide synthase 3 (NOS3) and also the inducible nitric oxide synthase gene (NOS2A) have been suggested to lead to increased risk of Alzheimer's disease (AD) or dementia with Lewy bodies. We have studied the relationship of both these NOS gene polymorphisms to development of AD and dementia with Lewy bodies and find no evidence for association with either condition. We conclude that NOS gene polymorphisms do not alter disease risk in the majority of late-onset dementia cases.
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PMID:Nitric oxide synthase gene polymorphisms in Alzheimer's disease and dementia with Lewy bodies. 1129 17

Neuronal nitric-oxide synthase (nNOS or NOS I) and endothelial NOS (eNOS or NOS III) differ widely in their reductase and nitric oxide (NO) synthesis activities, electron transfer rates, and propensities to form a heme-NO complex during catalysis. We generated chimeras by swapping eNOS and nNOS oxygenase domains to understand the basis for these differences and to identify structural elements that determine their catalytic behaviors. Swapping oxygenase domains did not alter domain-specific catalytic functions (cytochrome c reduction or H(2)O(2)-supported N(omega)-hydroxy-l-arginine oxidation) but markedly affected steady-state NO synthesis and NADPH oxidation compared with native eNOS and nNOS. Stopped-flow analysis showed that reductase domains either maintained (nNOS) or slightly exceeded (eNOS) their native rates of heme reduction in each chimera. Heme reduction rates were found to correlate with the initial rates of NADPH oxidation and heme-NO complex formation, with the percentage of heme-NO complex attained during the steady state, and with NO synthesis activity. Oxygenase domain identity influenced these parameters to a lesser degree. We conclude: 1) Heme reduction rates in nNOS and eNOS are controlled primarily by their reductase domains and are almost independent of oxygenase domain identity. 2) Heme reduction rate is the dominant parameter controlling the kinetics and extent of heme-NO complex formation in both eNOS and nNOS, and thus it determines to what degree heme-NO complex formation influences their steady-state NO synthesis, whereas oxygenase domains provide minor but important influences. 3) General principles that relate heme reduction rate, heme-NO complex formation, and NO synthesis are not specific for nNOS but apply to eNOS as well.
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PMID:Chimeras of nitric-oxide synthase types I and III establish fundamental correlates between heme reduction, heme-NO complex formation, and catalytic activity. 1131 63

Methods of reverse transcription polymerase chain reaction (RT-PCR), intrathecal injection and antisense drugs were used to study the effects of nitric oxide (NO) on the scores of morphine-withdrawal syndrome and the expression of NMDA1AR mRNA in rat spinal cord and brainstem. Intrathecal injection of NOS antisense oligonucleotides (AS-ONs) significantly decreased the scores of morphine-withdrawal symptoms. The effect of nNOS AS-ONs was greater than that of eNOS AS-ONs. The expression of NMDA1AR mRNA in the spinal cord and brainstem increased in morphine-dependent rats and increased to a greater extent in morphine-withdrawal rats. Intrathecal injection of nNOS AS-ONs significantly inhibited the increased expression of NMDA1AR mRNA in the spinal cord and brainstem of morphine-withdrawal rats. Intrathecal injection of eNOS antisense oligonucleotides inhibited the expression of NMDA1AR mRNA in the spinal cord of morphine-withdrawal rats, but did not in the brainstem. It is suggested that NO mediates morphine-withdrawal reaction and participates in modulating the expression of NMDA1AR mRNA in morphine-withdrawal rats.
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PMID:[Intrathecal injection of NOS antisense oligonucleotides inhibits the increase of NMDA1AR mRNA expression in the spinal cord and brainstem of morphine-withdrawal rats]. 1135 93

This study investigated the role of nitric oxide(NO) in the prevention of myocardial hypertrophic response and its mechanisms. Left ventricular NO content decreases in the pathophysiogenesis of myocardial hypertrophy induced by pressure overload. Endogenous NO may attenuate cardiac hypertrophy induced by pressure overload, independent of cGMP mechanism. Angiotensin II (AII), endothelin-1 (ET-1) and norepinephrine(NE) can inhibit NOS activity and NO production, and induce hypertrophic response in cultured neonatal rat cardiomyocytes; these effects of AII, ET-1 and NE are mediated respectively by AII receptor, ETA receptor and alpha 1-adrenergic receptor; these effects of AII and ET-1 are mediated by PTX-sensitive G protein, while the effects of NE are mediated by PTX-insensitive G protein. eNOS gene is expressed in cultured neonatal rat cardiac myocytes and nonmyocytes. AII, ET-1 and NE can inhibit eNOS gene expression in cardiomyocytes. Exogenous NO can prevent hypertrophic response induced by AII, ET-1 and NE in cardiomyocytes. Both endogenous and exogenous NO can inhibit the expression of proto-oncogene c-fos induced by AII and ET-1, which may be involved in protein kinase C.
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PMID:[The role of nitric oxide in the prevention of myocardial hypertrophic response and its mechanisms]. 1137 22

Decreased availability of arginine and impaired production of NO (nitric oxide) have been implicated in the development of endothelial dysfunction. Citrulline formed by the NOS reaction is recycled to arginine by the citrulline-NO cycle, which is composed of NOS, argininosuccinate synthetase (AS), and argininosuccinate lyase. Therefore, we investigated the alterations of these enzymes in the aorta of streptozotocin (STZ)-induced diabetic rats. eNOS and AS mRNAs were increased by three- to fourfold 1-2 weeks after STZ treatment and decreased at 4 weeks. AL mRNA was weakly induced. Induction of eNOS and AS proteins was also observed. Cationic amino acid transporter (CAT)-1 mRNA remained little changed, and CAT-2 mRNA was not detected. The plasma nitrogen oxide levels were increased 1-2 weeks after STZ treatment and decreased at 4 weeks. Transforming growth factor-beta1 (TGF-beta1) mRNA in the aorta was also induced. TGF-beta1 induced eNOS and AS mRNAs in human umbilical vein endothelial cells but inhibited the proliferation of HUVEC. These results indicate that eNOS and AS are coinduced in the aorta in early stages of STZ-induced diabetic rats and that the induction is mediated by TGF-beta1. The results also suggest that TGF-beta1 works antiatherogenically at early stages of diabetes by increasing NO production, whereas prolonged elevation of TGF-beta1 functions atherogenically by inhibiting endothelial cell growth.
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PMID:Coinduction of endothelial nitric oxide synthase and arginine recycling enzymes in aorta of diabetic rats. 1138 98

Mossy fiber long-term potentiation (mfLTP) was compared in hippocampal slices prepared from wild-type mice and mice lacking functional endothelial nitric oxide synthase (eNOS(-/-) mice) using field potential recording. In the presence of D-2-amino-5-phosphonovaleric acid (AP5, 50 microM), the mfLTP induced by tetanic stimulation (100 Hz, 1 sec) was significantly reduced in knockouts (n = 8) in comparison with wild-type (n = 8). Similarly, potentiation induced by forskolin (30 microM) or 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP, 100 microM) was less pronounced in knockouts. However, in wild-types the mfLTP-induced in the presence of the nonselective pharmacological inhibitor of NOS (N-nitro-L-Arginine, 100 microM, n = 6) was not significantly different from control (n = 8). Thus, eNOS is not directly involved in mfLTP, but lack of eNOS during development leads to a deficit downstream of adenylyl cyclase.
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PMID:Defective hippocampal mossy fiber long-term potentiation in endothelial nitric oxide synthase knockout mice. 1139 79


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