UMLS:C0406810 - FACTA Search

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

Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We measured the activity of mitogen-activated protein (MAP) kinases, enzymes believed to be involved in the pathway for cell proliferation, in rat aortic strips with or without endothelium, and examined effects of angiotensin receptor antagonists, endothelin receptor antagonists and nitric oxide (NO)-related agents. Endothelium removal produced an activation of MAP kinase activity in the strips, whereas the enzyme activity was not affected in the adventitia. The MAP kinase activation was inhibited by either the angiotensin AT1 receptor antagonist losartan or the endothelin ETA receptor antagonist BQ 123. The combination of both antagonists caused an additive inhibition. The angiotensin AT2 receptor antagonist PD 123,319 and the endothelin ETB receptor antagonist BQ 788 did not affect the MAP kinase activation. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) caused an activation of MAP kinase in the endothelium-intact aorta and the MAP kinase activation was inhibited by losartan or BQ123. The NO releaser nitroprusside inhibited the MAP kinase activation induced by endothelium removal or angiotensin II. These results suggest that even in isolated arteries, NO of endothelial origin tonically exert MAP kinase-inhibiting effects and endogenous angiotensin II and endothelins in the media are tonically released to cause MAP kinase-stimulating effects in medial smooth muscle.
...
PMID:Evidence that angiotensin II, endothelins and nitric oxide regulate mitogen-activated protein kinase activity in rat aorta. 965 1

The effects of elevated D-glucose on adenosine transport were investigated in human cultured umbilical vein endothelial cells isolated from normal pregnancies. Elevated D-glucose resulted in a time- (8-12 h) and concentration-dependent (half-maximal at 10+/-2 mM) inhibition of adenosine transport, which was associated with a reduction in the Vmax for nitrobenzylthioinosine (NBMPR)-sensitive (es) saturable nucleoside with no significant change in Km. d-Fructose (25 mM), 2-deoxy-D-glucose (25 mM) or D-mannitol (20 mM) had no effect on adenosine transport. Adenosine transport was inhibited following incubation of cells with the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA; 100 nM, 30 min to 24 h). D-Glucose-induced inhibition of transport was abolished by calphostin C (100 nM, an inhibitor of PKC), and was not further reduced by PMA. Increased PKC activity in the membrane (particulate) fraction of endothelial cells exposed to D-glucose or PMA was blocked by calphostin C but was unaffected by NG-nitro-L-arginine methyl ester (L-NAME; 100 microM, an inhibitor of nitric oxide synthase (NOS)) or PD-98059 (10 microM, an inhibitor of mitogen-activated protein kinase kinase 1). D-Glucose and PMA increased endothelial NOS (eNOS) activity, which was prevented by calphostin C or omission of extracellular Ca2+ and unaffected by PD-98059. Adenosine transport was inhibited by S-nitroso-N-acetyl-l, d-penicillamine (SNAP; 100 microM, an NO donor) but was increased in cells incubated with L-NAME. The effect of SNAP on adenosine transport was abolished by PD-98059. Phosphorylation of mitogen-activated protein kinases p44mapk (ERK1) and p42mapk (ERK2) was increased in endothelial cells exposed to elevated D-glucose (25 mM for 30 min to 24 h) and the NO donor SNAP (100 microM, 30 min). The effect of D-glucose was blocked by PD-98059 or L-NAME, which also prevented the inhibition of adenosine transport mediated by elevated D-glucose. Our findings provide evidence that D-glucose inhibits adenosine transport in human fetal endothelial cells by a mechanism that involves activation of PKC, leading to increased NO levels and p42-p44mapk phosphorylation. Thus, the biological actions of adenosine appear to be altered under conditions of sustained hyperglycaemia.
...
PMID:Regulation of adenosine transport by D-glucose in human fetal endothelial cells: involvement of nitric oxide, protein kinase C and mitogen-activated protein kinase. 1111 5

Circulating tumor necrosis factor alpha (TNF-alpha) has a profound stimulatory influence on mitogen-activated protein kinases that lead to nuclear factor kappa B (NF-kappaB) activity and transcription of the cyclooxygenase 2 (COX-2) gene in cells associated with the blood-brain barrier (BBB). This study investigated the hypothesis that nitric oxide (NO) acts as an endogenous modulator of TNF-induced NF-kappaB signaling and COX-2 transcription in the endothelium of the cerebral capillaries. To this end, rats were pretreated with the nonselective inhibitor of NO synthase (NOS) N(G)-nitro-L-arginine methyl ester (L-NAME) and killed 15, 45, and 90 minutes (min) after an i.v. injection of recombinant rat TNF-alpha. De novo expression of the inhibitory factor kappa B alpha (IkappaB alpha) was used as an index of NF-kappaB activity, whereas COX-2 mRNA induction was evaluated throughout the brain by in situ hybridization combined with immunohistochemistry. A single i.v. bolus of TNF caused a rapid expression of IkappaB alpha transcript first along large arterioles and small capillaries and thereafter within microglia across the brain parenchyma. The proinflammatory cytokine also provoked a strong transcriptional activation of the COX-2 gene that was quite specific to the cerebral endothelium as revealed by dual labeling using an antisera directed against the von Willebrand factor. Inhibition of NO synthesis did not by itself activate these proinflammatory molecules, but it enhanced the effects of circulating TNF-alpha in the BBB; the IkappaB alpha and COX-2 signal was significantly higher in microvascular-associated cells of animals that received both L-NAME and TNF-alpha treatments than those challenged with the proinflammatory cytokine alone. Rats treated with specific NOS inhibitors provided the evidence that these effects were mediated via the constitutive endothelial NOS (eNOS) and not the inducible form. These results indicate that eNOS-derived NO acts as an endogenous inhibitor of TNF-alpha-induced NF-kappaB activity and COX-2 transcription in the endothelium of the cerebral capillaries. This autoregulatory feedback of NO on these proinflammatory signal transduction events may be an essential element to prevent an exaggerated response that takes place in cells of the BBB during systemic immune challenges.
...
PMID:Inhibitory action of nitric oxide on circulating tumor necrosis factor-induced NF-kappaB activity and COX-2 transcription in the endothelium of the brain capillaries. 1155 46

Leptin regulates cardiovascular function. Leptin levels are elevated in obesity and hypertension and may play a role in cardiovascular dysfunctions in these comorbidities. This study was designed to determine the influence of hypertension on the cardiac contractile response of leptin. Mechanical and intracellular Ca(2+) properties were evaluated using an IonOptix system in ventricular myocytes from spontaneously hypertensive (SHR) and age-matched Wistar Kyoto (WKY) rats. The contractile properties included peak shortening (PS), duration and maximal velocity of shortening/relengthening (TPS/TR(90), +/-dL/dt), and fura-fluorescence intensity change (DeltaFFI). NO and nitric oxide synthase (NOS) activity were assessed by the Griess and the (3)H-arginine/citrulline conversion assays, respectively. The leptin receptor (Ob-R) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway were evaluated by Western blot analysis. SHR animals displayed significantly elevated blood pressure and plasma leptin levels. Leptin elicited a concentration-dependent inhibition of PS and DeltaFFI in WKY, but not in SHR myocytes. Leptin did not affect TPS, TR(90), or +/- dL/dt. The difference in leptin-induced contractile response between the WKY and the SHR groups was abolished by the NOS inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), but not by elevated extracellular Ca(2+). Either the JAK2 inhibitor AG-490 or the mitogen-activated protein (MAP) kinase inhibitor SB203580 abrogated the leptin-induced response in the WKY myocytes, whereas AG-490 unmasked a negative response in PS in the SHR myocytes. SHR myocytes displayed similar Ob-R protein abundance and basal NO levels, a blunted leptin-induced increase in NOS activity as well as enhanced basal STAT3 levels compared with the WKY group. These data indicate that the leptin-induced cardiac contractile response is abolished by spontaneous hypertension, possibly because of mechanisms involving altered JAK/STAT, MAP kinase signaling, and NO response.
...
PMID:Abrogated leptin-induced cardiac contractile response in ventricular myocytes under spontaneous hypertension: role of Jak/STAT pathway. 1179 81

Adenosine is released from the myocardium, endothelial cells, and skeletal muscle in ischemia and is an important regulator of coronary blood flow. We have already shown that acute (2 min) activation of A2a purinoceptors stimulates NO production in human fetal umbilical vein endothelial cells (1) and now report a key role for p42/p44 mitogen-activated protein kinases (p42/p44MAPK) in the regulation of the l-arginine-nitric oxide (NO) signaling pathway. Expression of mRNA for the A2a-, A2b-, and A3-adenosine receptor subtypes was abundant whereas A1-adenosine receptor mRNA levels were negligible. Activation of A2a purinoceptors by adenosine (10 microM) or the A2a receptor agonist CGS21680 (100 nM) resulted in an increase in l-arginine transport and NO release that was not mediated by changes in intracellular Ca2+, pH, or cAMP. Stimulation of endothelial cells with adenosine was associated with a membrane hyperpolarization and phosphorylation of p42/p44MAPK. l-NAME abolished the adenosine-induced hyperpolarization and stimulation of l-arginine transport whereas sodium nitroprusside activated an outward potassium current. Genistein (10 microM) and PD98059 (10 microM), an inhibitor of MAPK kinase 1/2 (MEK1/2), inhibited adenosine-stimulated l-arginine transport, NO production, and phosphorylation of p42/p44MAPK. We found no evidence for activation of eNOS via the serine/threonine kinase Akt/PKB (protein kinase B) in adenosine-stimulated cells. Our results provide the first evidence that adenosine stimulates the endothelial cell l-arginine-NO pathway in a Ca2+-insensitive manner involving p42/p44MAPK, with release of NO leading to a membrane hyperpolarization and activation of l-arginine transport.
...
PMID:Early activation of the p42/p44MAPK pathway mediates adenosine-induced nitric oxide production in human endothelial cells: a novel calcium-insensitive mechanism. 1237 81

An elevated extracellular concentration of D-glucose (i.e. hyperglycaemia) inhibits cell proliferation and incorporation of the endogenous nucleoside thymidine into DNA in human umbilical vein endothelial cells (HUVECs). Cells in their log-phase of growth (3.7 +/- 0.3 days, n = 27) incubated for 30 min with 25 mM D-glucose, but not with equimolar concentrations of L-glucose or D-mannitol, exhibited reduced [3H]thymidine incorporation and cell growth rate, with no change in cell viability (> 98 %), total DNA, protein content or cell volume. Incubation with D-glucose activated protein kinase C (PKC), endothelial NO synthase (eNOS), p42 and p44 mitogen-activated protein kinases (p42/44(mapk)), but inhibited superoxide dismutase (SOD). Incubation with D-glucose also increased cGMP and cAMP levels. The effect of D-glucose was blocked by the PKC inhibitor calphostin C, the MAP kinase kinase 1/2 (MEK1/2) inhibitor PD-98059, the eNOS inhibitor L-NAME, the protein kinase G (PKG) inhibitor KT-5823 and the protein kinase A (PKA) inhibitor KT-5720. In the presence of 5 mM D-glucose, [3H]thymidine incorporation and cell growth were reduced by the PKC activator phorbol 12-myristate 13-acetate (PMA), the NO donor S-nitroso-N-acetyl-L,D-penicillamine (SNAP), dibutyryl cGMP, dibutyryl cAMP and the Ca2+ ionophore A-23187. The effect of A-23187 was blocked by calphostin C and PD-98059. D-Glucose-dependent inhibition of thymidine incorporation and cell proliferation is associated with increased PKC, eNOS, and MEK1/2, but decreased SOD activity, and higher intracellular levels of cGMP, cAMP and Ca2+ in HUVECs. These are cellular mechanisms which may reduce endothelial cell growth in pathological conditions such as in diabetes mellitus or hyperglycaemia.
...
PMID:Hyperglycaemia inhibits thymidine incorporation and cell growth via protein kinase C, mitogen-activated protein kinases and nitric oxide in human umbilical vein endothelium. 1262 26

17beta-estradiol reduces myocardial hypertrophy and left ventricular mass, suggesting that the selective estrogen receptor modulator raloxifene may have similar effects. However, it is not clear whether raloxifene inhibits both cardiac hypertrophy and dysfunction. We used transverse aortic-banded mice to produce pressure-overload cardiac hypertrophy and used neonatal rat ventricular cardiomyocytes to investigate the cellular mechanisms of raloxifene on cardiac hypertrophy. Left ventricular mass and fractional shortening of mice hearts were measured by transthoracic echocardiography. Protein synthesis of cardiomyocytes was evaluated by incorporation of [3H]leucine into cardiomyocytes exposed to angiotensin II. Phosphorylation of mitogen-activated protein (MAP) kinase was also observed in cardiomyocytes. Raloxifene prevented increases in left ventricular mass and decreases of fractional shortening at 4 weeks after aortic banding. Pretreatment with raloxifene before angiotensin II stimulation inhibited the increase in [3H]leucine incorporation into neonatal rat cardiomyocytes in a concentration-dependent manner. This inhibition was partially but not significantly attenuated by N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, and completely abolished by ICI182780, an estrogen receptor antagonist. Although the phosphorylation of p38 MAP kinase, c-Jun N-terminal kinase (JNK), or extracellular signal-regulated protein kinase (ERK) in cardiomyocytes was significantly increased by angiotensin II stimulation as compared with the control, pretreatment with raloxifene attenuated p38 MAP kinase phosphorylation, but neither JNK nor ERK phosphorylation. We conclude that raloxifene inhibits cardiac hypertrophy and dysfunction and that the inhibition of p38 MAP kinase phosphorylation after the stimulation of estrogen receptors may be involved in the cellular mechanisms of this agent.
...
PMID:Raloxifene prevents cardiac hypertrophy and dysfunction in pressure-overloaded mice. 1467 19

The enhanced production of nitric oxide (NO) via inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of neuronal apoptosis after acute traumatic spinal cord injury (SCI). In the present study, to further characterize the pathways mediating the synthesis and release of NO, we examined activation of extracellular signal regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinases (p38 MAPK) in microglia/macrophages in the injured area of adult rats subjected to a complete transection at the T10 vertebrae level and assessed their role in NO production and survival of neurons by using immunohistochemistry, Western blot, RT-PCR and pharmacological interventions. Results showed activation of microglia/macrophages featured by morphological changes, as visualized immunohistochemically with the marker OX-42, in the areas adjacent to the lesion epicenter 1 h after surgery. Concomitantly, iNOS mRNA and its protein in the activated microglia/macrophages were also significantly upregulated at early hours after surgery. Their levels were maximal at 6 h, persisted for at least 24 h, and returned to basal level 72 h after SCI. Furthermore, phosphorylated ERK1/2 and p38 MAPK were activated as well in microglia/macrophages in injured area with a similar time course as iNOS. With administration of L-NAME, a NOS inhibitor, the number of apoptotic neurons was clearly decreased, as assessed with TUNEL method at 24 h after SCI. In parallel, loss of neurons induced by SCI, assessed with NeuN immunohistochemistry, was also diminished. Moreover, the effect of inhibition of phosphorylation ERK1/2 and p38 MAPK by corresponding inhibitors PD98059 and SB203580 administered before and after SCI was also investigated. Inhibition of p38 effectively reduced iNOS mRNA expression and rescued neurons from apoptosis and death in the area adjacent to the lesion epicenter; whereas the inhibition of ERK1/2 had a smaller effect on decrease of iNOS mRNA and no long-term protective effect on cell loss. These results indicate the ERK1/2 and p38 MAPK signaling pathway, especially the latter, play an important role in NO-mediated degeneration of neuron in the spinal cord following SCI. Strategies directed to blocking the initiation of this cascade prove to be beneficial for the treatment of acute SCI.
...
PMID:ERK1/2 and p38 mitogen-activated protein kinase mediate iNOS-induced spinal neuron degeneration after acute traumatic spinal cord injury. 1697 58

Nerve growth factor (NGF) can regulate nitric oxide synthase (NOS) expression and nitric oxide (NO) can modulate NGF-mediated neurotrophic responses. In this study, the role of NO in NGF-stimulated amyloid precursor protein (APP) levels was studied. PC12 cells were treated with either the non-selective NOS inhibitor N(omega)-nitro-L-arginine methylester (L-NAME) or the inducible NOS selective inhibitor s-methylisothiourea (S-MIU), and the effect on NGF-mediated increases in APP expression was determined. NGF significantly increased total APP protein levels following 96 h of treatment and this increase was prevented in cells pre-treated with S-MIU. Pre-treatment of cells with actinomycin D also blocked this NGF-mediated induction of APP, indicating de novo protein synthesis is necessary. Treatment with NGF increased APP promoter activity; however, this increase was only partially inhibited by pre-treatment with S-MIU and was increased in the presence of L-NAME. This suggests that NO may be modulating other aspects of APP expression in addition to transcription. Inhibition of NGF signaling pathways was also investigated using inhibitors of mitogen-activated protein (MAP) kinase (U0126), Akt (LY294002) and protein kinase C (PKC; U73122 and bisindolylmaleimide 1 (BIS-1)) activation. Inhibition of each of these pathways prevented NGF-mediated increases in APP protein expression; however, only BIS-1 attenuated NGF-mediated increases in promoter activation. This study indicates that NO is involved in the NGF-mediated regulation of APP, in part at the level of APP transcription and could involve the modulation of NGF signal transduction pathways.
...
PMID:Nitric oxide synthase inhibitors modulate nerve growth factor-mediated regulation of amyloid precursor protein expression in PC12 cells. 1740 71

Angiotensin II (ANG II) is a powerful activator of mitogen-activated protein (MAP) kinase cascades in cardiovascular tissues through a redox-sensitive mechanism. Nitric oxide (NO) is considered to antagonize the vasoconstrictive and proarteriosclerotic actions of ANG II. However, the role of endogenous NO in ANG II-induced redox-sensitive signal transduction is not yet clear. In this study using catheterized, conscious rats, we found that acute intravenous administration of N(G)-nitro-L-arginine methyl ester (L-NAME; 5 mg/kg) enhanced phosphorylation of aortic MAP kinases extracellular signal regulated kinase (ERK) 1/2 and p38, which were suppressed only partially by a superoxide dismutase mimetic (Tempol), whereas ANG II-induced MAP kinase phosphorylation was markedly suppressed by Tempol. FK409, a NO donor, had little effect on vascular MAP kinase phosphorylation. On the other hand, acute exposure to a vasoconstrictor dose of ANG II (200 ng x kg(-1) x min(-1) iv) failed to enhance phosphorylation of aortic MAP kinases in the chronically L-NAME-treated rats, whereas the vasoconstrictor effect of ANG II was not affected by L-NAME treatment. Furthermore, three different inhibitors of NO synthase suppressed, in a dose-dependent manner, ANG II-induced MAP kinase phosphorylation in rat vascular smooth muscle cells, which was closely linked to superoxide generation in cells. These results indicate the involvement of endogenous NO synthase in ANG II-induced signaling pathways, leading to activation of MAP kinase, and that NO may have dual effects on the vascular MAP kinase activation associated with redox sensitivity.
...
PMID:Involvement of endogenous nitric oxide in angiotensin II-induced activation of vascular mitogen-activated protein kinases. 1761 51

1 2 Next >>