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:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased incidence of myocardial infarction was found in hypertensive patients with high plasma renin activity and increased susceptibility to oxidation was demonstrated in low density lipoprotein (LDL) that was obtained from hypertensive patients. As lipid peroxidation was demonstrated in areas of the atherosclerotic lesion, we sought to analyze the effect of angiotensin II (AN-II) on LDL oxidation, both in vitro and in vivo. Preincubation of J-774 A.1 macrophage-like cell line or mouse peritoneal macrophages (MPM) with AN-II (10(-7) M) for 1 h at 37 degrees C, followed by the addition of LDL for a further 18 h of incubation, resulted in a substantial increase in macrophage-mediated oxidation of LDL (by 55% and 19%, respectively). Similarly, incubation of LDL with MPM harvested from AN-II-injected mice resulted in a substantially increased oxidation of the lipoprotein by up to 90% in comparison to saline-injected mice. Analysis of cellular lipid peroxidation in the MPM themselves, in both the in vitro and the in vivo studies, revealed a 25% or 90% increased macrophage lipid peroxidation, respectively. The mechanism of AN-II-mediated cellular lipid peroxidation involved AN-II binding to its receptor on macrophages as saralasin, an AN-II receptor antagonist, completely inhibited this effect. Inhibitors of phospholipases A2, C and D substantially reduced macrophage lipid peroxidation, suggesting the involvement of phospholipases A2, C and D substantially reduced macrophage lipid peroxidation, suggesting the involvement of phospholipid metabolites in AN-II-mediated macrophage lipid peroxidation, suggesting the involvement of phospholipid metabolites in AN-II-mediated macrophage lipid peroxidation. Extracellular calcium ions, which active phospholipases, were also essential for AN-II-mediated macrophage lipid peroxidation since calcium channel blockers substantially inhibited cellular lipid peroxidation. Finally, the nature of the oxidant and oxygenase involved in AN-II-mediated cellular lipid peroxidation was studied using oxygenase inhibitors. Angiotensin II-mediated macrophage lipid peroxidation was found to involve the action of cellular NADPH oxidase as well as 15-lypoxygenase. We conclude that AN-II stimulates macrophage-mediated mediated oxidation of LDL secondary to cellular lipid peroxidation, and this may have a role in the accelerated atherosclerosis found in hypertensive patients.
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PMID:Angiotensin II stimulates macrophage-mediated oxidation of low density lipoproteins. 766 79

Angiotensin II is a multifunctional hormone that affects both contraction and growth of vascular smooth muscle cells through a complex series of intracellular signaling events initiated by the interaction of angiotensin II with the AT1 receptor. The cellular response to angiotensin II is multiphasic, involving stimulation within seconds of phospholipase C and Ca2+ mobilization; activation within minutes of phospholipase D, A2, protein kinase C, and MAP kinase; and stimulation after a period of hours of gene transcription and NADH/NADPH oxidase activity. Angiotensin II also activates numerous intracellular tyrosine kinases. In this respect, it shares some aspects of signaling with growth factor and cytokine receptors, including activation of phospholipase C-gamma, src, and ras; association of shc with grb2; and stimulation of the Jak/STAT pathway. The cellular events responsible for this unique series of events may involve receptor movement and the creation of a signaling domain. Elucidation of these pathways is important to our understanding of AT1 receptor function as a final effector of the renin-angiotensin system.
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PMID:Angiotensin II signaling in vascular smooth muscle. New concepts. 903 29

Monocyte infiltration into the vessel wall, a key initial step in the process of atherosclerosis, is mediated in part by monocyte chemoattractant protein-1 (MCP-1). Hypertension, particularly in the presence of an activated renin-angiotensin system, is a major risk factor for the development of atherosclerosis. To investigate a potential molecular basis for a link between hypertension and atherosclerosis, we studied the effects of angiotensin II (Ang II) on MCP-1 gene expression in rat aortic smooth muscle cells. Rat smooth muscle cells treated with Ang II exhibited a dose-dependent increase in MCP-1 mRNA accumulation that was prevented by the AT1 receptor antagonist losartan. Ang II also activated MCP-1 gene transcription. Inhibition of NADH/NADPH oxidase, which generates superoxide and H2O2, with diphenylene iodonium or apocynin decreased Ang II-induced MCP-1 mRNA accumulation. Induction of MCP-1 gene expression by Ang II was inhibited by catalase, suggesting a second messenger role for H2O2. The tyrosine kinase inhibitor genistein and the mitogen-activated protein kinase kinase inhibitor PD098059 inhibited Ang II-induced MCP-1 gene expression, consistent with a mitogen-activated protein kinase-dependent signaling mechanism. Ang II may thus promote atherogenesis by direct activation of MCP-1 gene expression in vascular smooth muscle cells.
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PMID:Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells. 979 45

Angiotensin II and hypertension increase vascular oxidant stress. We examined how these might affect expression of the extracellular superoxide dismutase (ecSOD), a major form of vascular SOD. In mice, angiotensin II infusion (1.1 mg/kg for 7 days) increased systolic blood pressure from 107+/-3 to 152+/-9 mm Hg and caused a 3-fold increase in ecSOD, but there was no change in the cytosolic Cu/Zn SOD protein, as determined by Western blot analysis. This was associated with a similar increase in ecSOD mRNA as assessed by RNase protection assay and was prevented by losartan. Induction of ecSOD by angiotensin II was not due to hypertension alone, because hypertension caused by norepinephrine (5.6 mg. kg-1. d-1) had no effect on ecSOD. Similarly, exposure of mouse aortas to angiotensin II (100 nmol/L) in organoid culture increased ecSOD by approximately 2-fold. In the organoid culture, angiotensin II-induced upregulation of ecSOD was prevented by losartan (10 micromol/L) and PD985059 (30 micromol/L), a specific inhibitor of p42/44 MAP kinase kinase. Angiotensin II activates the NADH/NADPH oxidase; however, diphenyleneiodonium chloride (10 micromol/L), an inhibitor of this oxidase, did not prevent p42/44 MAP kinase phosphorylation or ecSOD induction by angiotensin II. Finally, in human aortic smooth muscle cells, angiotensin II moderately increased transcriptional rate (as assessed by nuclear run-on analysis) but markedly increased ecSOD mRNA stability. Thus, angiotensin II increases ecSOD expression independent of hypertension, and this increase involves both an increase in ecSOD transcription and stabilization of ecSOD mRNA. This effect of angiotensin II on ecSOD expression may modulate the oxidative state of the vessel wall in pathological processes in which the renin-angiotensin system is activated.
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PMID:Modulation of extracellular superoxide dismutase expression by angiotensin II and hypertension. 1040 Sep 7

The atherogenic effect of the renin-angiotensin system can be explained, in part, by the influence of its effector, angiotensin II (Ang II), on vascular smooth muscle cell (VSMC) growth. There is evidence that reactive oxygen species (ROS) play a role in the atherogenesis and activation of mitogen-activating protein (MAP) kinases, which are involved in proliferation and differentiation. The study was performed to further characterize the role of ROS in Ang II-mediated MAP kinase activation and the regulation of the transcription factor activator protein-1 (AP-1). Rat VSMCs were stimulated with Ang II. The activities of MAP kinases were assessed by Western blot analysis or by immunocomplex kinase assay. AP-1 binding was determined by using an electrophoretic mobility shift assay. Rat VSMCs were treated with Ang II-activated MAP kinases, extracellular signal-regulated kinase (ERK), c-Jun amino terminal kinase (JNK), p38 MAP kinase (p38 MAPK), and their downstream effector, AP-1. Interestingly, only the activation of ERK1/2, but not JNK or p38 MAPK, was tyrosine kinase, protein kinase C, and MEK1/2 dependent. Ang II also induced the rapid formation of ROS, which could be inhibited by a specific antibody as well as by antisense against the p22phox subunit of the NAD(P)H oxidase. JNK and p38 MAPK, but not ERK, activation was inhibited by an inhibitor of NAD(P)H oxidase. Antisense against p22phox also solely inhibited p38 MAPK but did not affect ERK. The results indicate that in VSMCs, Ang II activates MAP kinases and AP-1 through different pathways; the results further suggest that ROS, generated by p22phox, mediate Ang II-induced JNK and p38 MAPK activation, which may contribute to the pathogenesis of atherosclerosis.
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PMID:Differential activation of mitogen-activated protein kinases in smooth muscle cells by angiotensin II: involvement of p22phox and reactive oxygen species. 1076 57

Angiotensin II stimulates a plethora of signaling pathways leading to cell growth and contraction. Recent work has shown that reactive oxygen species are involved in transducing many of the effects of angiotensin II, and are in fact produced in response to agonist-receptor binding. Angiotensin II stimulates a NAD(P)H oxidase to produce superoxide and hydrogen peroxide, both of which may act on intracellular growth-related proteins and enzymes to mediate the final physiological response. Of particular importance is hydrogen peroxide, which mediates angiotensin II stimulation of such important intracellular signals as EGF-receptor transactivation, p38 mitogen activated protein kinase, and Akt. Future work will be directed towards identifying other important redox-sensitive signaling pathways and their relationship to the physiology and pathophysiology of the renin-angiotensin system.
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PMID:Reactive oxygen species as mediators of angiotensin II signaling. 1096 99

Cardiac hypertrophy as an adaptation to increased blood pressure leads to an increase in ventricular expression of transforming growth factor Cardiac hypertrophy as an adaptation to increased blood pressure leads to an increase in ventricular expression of transforming growth factor b (TGF-b), probably via the renin-angiotensin system. We studied in vivo to determine whether angiotensin II affects TGF-b expression independent from mechanical effects caused by the concomitant increase in blood pressure and in vitro intracellular signaling involved in angiotensin II-dependent TGF-b1 induction. In vivo, the AT1 receptor antagonist losartan, but not reduction of blood pressure by hydralazine, inhibited the increase in TGF-b1 expression caused by angiotensin II. In vitro, angiotensin II caused an induction of TGF-b1 expression in adult ventricular cardiomyocytes and induced AP-1 binding activity. Transfection with "decoys" directed against the binding site of AP-1 binding proteins inhibited the angiotensin II-dependent TGF-b induction. Angiotensin II induced TGF-b expression in a p38-MAP kinase-dependent way. p38-MAP kinase activation was diminished in presence of the antioxidants or diphenyleneiodium chloride, or by pretreatment with antisense nucleotides directed against phox22 and nox, components of smooth muscle type NAD(P)H oxidase. Thus, our study identifies a previously unrecognized coupling of cardiac AT receptors to a NAD(P)H oxidase complex similar to that expressed in smooth muscle cells and identifies p38-MAP kinase activation as an important downstream target.
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PMID:Redox-sensitive intermediates mediate angiotensin II-induced p38 MAP kinase activation, AP-1 binding activity, and TGF-beta expression in adult ventricular cardiomyocytes. 1151 16

The renin-angiotensin system has long been recognized as crucial factor in the regulation of the systemic blood pressure and renal electrolyte homeostasis. Numerous studies have demonstrated the presence of a local renin-angiotensin system in a variety of organs. A recent study of the pancreatic renin-angiotensin system showed that chronic hypoxia significantly increased the mRNA expression for angiotensinogen II receptor subtypes AT1b and AT2. The activation of the renin-angiotensin system may play an important role in cellular pathophysiological processes. Angiotensin II enhances the formation of reactive oxygen species via the activation of xanthine oxidase or NAD(P)H oxidase. The reactive oxygen species can cause oxidative damage in the pancreas and other tissues either directly or indirectly via the formation of other radicals such as reactive nitrogen species. Rhodiola therapy may protect hypoxia-induced pancreatic injury in two ways. It prevents hypoxia-induced biological changes by increasing intracellular oxygen diffusion and efficiency of oxygen utilization. Alternatively, it reduces hypoxia-induced oxidative damage by its antioxidant activities. Additional experimental data are required to fully elucidate the mode of action of this herbal drug.
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PMID:Association of free radicals and the tissue renin-angiotensin system: prospective effects of Rhodiola, a genus of Chinese herb, on hypoxia-induced pancreatic injury. 1186 18

The effect of ACE inhibition on the formation of advanced glycation end products (AGEs) and oxidative stress was explored. Streptozocin-induced diabetic animals were randomized to no treatment, the ACE inhibitor ramipril (3 mg/l), or the AGE formation inhibitor aminoguanidine (1 g/l) and followed for 12 weeks. Control groups were followed concurrently. Renal AGE accumulation, as determined by immunohistochemistry and both serum and renal fluorescence, were increased in diabetic animals. This was attenuated by both ramipril and aminoguanidine to a similar degree. Nitrotyrosine, a marker of protein oxidation, also followed a similar pattern. The receptor for AGEs, gene expression of the membrane-bound NADPH oxidase subunit gp91phox, and nuclear transcription factor-kappaB were all increased by diabetes but remained unaffected by either treatment regimen. Two other AGE receptors, AGE R2 and AGE R3, remained unchanged for the duration of the study. The present study has identified a relationship between the renin-angiotensin system and the accumulation of AGEs in experimental diabetic nephropathy that may be linked through oxidative stress
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PMID:Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy. 1240 19

Angiotensin II (Ang II) is a potent vasoconstrictor in the peripheral circulation and has been implicated in many cardiovascular diseases associated with elevated oxidative stress. However, its direct vasomotor action and its linkage to oxidative stress-induced vascular dysfunction in the coronary microcirculation remain elusive. In this study, we directly assessed the vasomotor action of Ang II in isolated porcine coronary arterioles and also examined whether Ang II can modulate endothelium-dependent nitric oxide (NO)-mediated dilation via superoxide production. Ang II evoked vasoconstriction at a low concentration (1 nmol/L) and dilations at higher concentrations (>10 nmol/L). Ang II type 1 (AT(1)) receptor antagonist losartan abolished vasoconstriction, whereas Ang II type 2 (AT(2)) receptor antagonist PD 123319 eliminated vasodilation. Adenosine stimulated a significant arteriolar NO production and dilation. NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) abolished stimulated NO production and attenuated vasodilation. Pretreating vessels with a subvasomotor concentration of Ang II (0.1 nmol/L, 60 minutes) mimicked inhibitory effects of L-NMMA. Ang II-mediated inhibition was not observed in the presence of L-NMMA or after endothelial removal but was prevented by losartan, superoxide scavenger TEMPOL, or NADPH oxidase inhibitor apocynin. Dihydroethidium staining showed that Ang II elicited losartan- and TEMPOL-sensitive superoxide production in arterioles. These results demonstrate that Ang II evokes AT1 receptor-mediated vasoconstriction and AT2 receptor-mediated vasodilation of coronary arterioles. Ang II at a subvasomotor level impairs endothelium-dependent NO-mediated dilation attributable to elevated superoxide production via AT1 receptor activation of NADPH oxidase. These data may partly explain the impaired coronary flow regulation in heart diseases associated with an upregulated renin-angiotensin system.
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PMID:Divergent roles of angiotensin II AT1 and AT2 receptors in modulating coronary microvascular function. 1259 45


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