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)

They were more than just another kinases (JAK), when they were first described in the late 80s and named JAK kinases. The mandatory role of this novel family of dual active janus kinases (JAK) and their substrates the signal transducers and activators of transcription (STAT) was demonstrated in mice who died during embryogenesis when lacking a functional allele, e.g. that of JAK2. Initially, the JAK/STAT signaling pathway was discovered as the primary mediator of intracellular signaling induced by interferon in hematopoietic and immune cells. Nowadays, it is well accepted that JAK kinases and STAT proteins are constitutively expressed in the vessel wall in a cell type specific manner and transfer intracellular signaling events of various receptor families, e.g. that of cytokines, growth factors and vasoactive peptides such as angiotensin II (Ang II) or endothelin. The potential impact of the JAK/STAT signaling pathway on cardiovascular pathophysiology and disease development arise from reports describing that JAKs may bind directly to the angiotensin II type I (AT(1)) receptor, thereby enhancing their phosphorylation in various cell types of the vessel wall. More interestingly, these signaling events are modulated by NAD(P)H oxidase-derived superoxide anions which directly phosphorylate JAK2 and thereby control JAK2 activity. A potential impact was also described for atherosclerotic plaque development in which the activation of JAKs and STATs seems to be critical. Based on these observations, we here review the role of the JAK/STAT signaling pathways as critical regulator for cardiovascular disease development, i.e. atherosclerotic plaque progression or the manifestation of arterial hypertension.
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PMID:JANUS under stress--role of JAK/STAT signaling pathway in vascular diseases. 1627 17

Endothelial dysfunction (ED) complicates hypertension and is a precursor of atherosclerosis. Reduced NO bioactivity, because of increased reduced NAD(P)H oxidase-derived reactive oxygen species (ROS), plays a critical role in ED. gp91phox, predominantly expressed in the endothelium and adventitia, is a subunit of NAD(P)H oxidase important for its activation in response to angiotensin (Ang) II. Human atherosclerotic plaques are heavy laden with gp91phox. We have shown that in Dahl salt-sensitive (DS) rats, a paradigm of low renin salt-sensitive (SS) hypertension in humans, Ang II receptor blockade normalizes ROS production and endothelium-dependent relaxation (EDR) without significantly affecting systolic blood pressure (SBP). To additionally elucidate the mechanisms involved in the functional association of Ang II in SS hypertension, we administered a cell-permeable inhibitor of the assembly of p47phox with gp91phox in NAD(P)H oxidase, gp91ds-tat (10 mg/kg body weight, 3 weeks by minipump), to DS rats fed a 4% salt diet. Control rats received either vehicle or an inactive scramb-tat peptide. Vehicle-treated DS developed hypertension (SBP 168+/-5 mm Hg), left ventricular hypertrophy (LVH), proteinuria, impaired EDR, and increased aortic ROS production (superoxide 115% and peroxynitrite 157%) and expression of the proatherogenic molecules LOX-1 (130%) and MCP-1 (166%). gp91ds-tat, but not scramb-tat, normalized ROS and EDR, as well as LOX-1 and MCP-1, despite nonsignificant effects on SBP (159+/-5 mm Hg; P>0.05), left ventricular hypertrophy, and proteinuria. Our findings support the notion that in SS hypertension, activation of NAD(P)H oxidase promotes ED and atherogenesis via decreased nitric oxide bioactivity and increased LOX-1 and MCP-1, independent of blood pressure.
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PMID:Reduced NAD(P)H oxidase in low renin hypertension: link among angiotensin II, atherogenesis, and blood pressure. 1634 66

The angiotensin II (Ang II) slow-pressor response entails an increase in mean arterial pressure and reactive oxygen species. We used double-stranded interfering RNAs (siRNAs) in Sprague Dawley rats in vivo to test the hypothesis that an increase in the p22phox component of NADPH oxidase is required for this response. Reactive oxygen species were assessed from excretion of 8-isoprostane prostaglandin F2alpha and blood pressure by telemetry. Two siRNA sequences to p22phox (sip22phox) reduced mRNA >85% in cultured vascular smooth muscle cells. Rats received rapid (10 second) IV injections (50 to 100 microg) of 1 of 2 different sip22phox, control siRNA, or vehicle (TransIt in saline) during 14 day SC infusions of Ang II (200 ng.kg(-1).min(-1)) or sham infusions. In both groups, sip22phox, relative to control siRNA, led to significant (P<0.001; approximately 50%) reductions in expression of p22phox mRNA and protein and of NADPH oxidase activity in the kidney cortex. In Ang II-infused rats, sip22phox decreased protein expression for Nox-1, -2, and -4 but increased p47phox. Three days after sip22phox, conscious rats infused with Ang II had a reduced excretion of 8-isoprostane (10+/-1 versus 19+/-2 pg.24 h(-1); P<0.01) and a reduced mean arterial pressure (142+/-5 versus 168+/-4 mm Hg; P<0.005). An increase in p22phox is required for increased renal NADPH oxidase activity, expression of Nox proteins and oxidative stress, and contributes < or =50% to hypertension during an Ang II slow-pressor response.
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PMID:RNA silencing in vivo reveals role of p22phox in rat angiotensin slow pressor response. 1639 Nov 71

Angiotensin II (Ang II) has been found to exert preconditioning-like effect on mammalian hearts. Diverse mechanisms are known to exist to explain the cardioprotective abilities of Ang II preconditioning. The present study hypothesized, based on the recent report that Ang II generates reactive oxygen species (ROS) through NADPH oxidase, that Ang II preconditioning occurs through redox cycling. To test this hypothesis, a group of rat hearts was treated with Ang II in the absence or presence of an NADPH oxidase inhibitor, apocynin; or a cell-permeable ROS scavenger, N-acetyl cysteine (NAC). Ang II pretreatment improved postischemic ventricular recovery; reduced myocardial infarction; and decreased the number of cardiomyocyte apoptosis, indicating its ability to precondition the heart against ischemic injury. Both apocynin and NAC almost abolished the preconditioning ability of Ang II. Ang II resulted in increase in ROS activity in the heart, which was reduced by either NAC or apocynin. Ang II also increased both the NADPH oxidase subunits gp91 phox and p22phox mRNA expression, which was abolished with apocynin and NAC. Our results thus demonstrate that the Ang II preconditioning was associated with enhanced ROS activities and increased NADPH oxidase subunits p22phox and gp91phox expression. Both NAC and apocynin reduced ROS activities simultaneously abolishing preconditioning ability of Ang II, suggesting that Ang II preconditioning occurs through redox cycling. That both NAC and apocynin reduced ROS activities and abolished Ang II-mediated increase in p22phox and gp91phox activity further suggest that such redox cycling occurs via both NADPH oxidase-dependent and -independent pathways.
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PMID:Angiotensin preconditioning of the heart: evidence for redox signaling. 1645 38

Angiotensin II (Ang II) and reactive oxidative species (ROS) that are produced by NADPH oxidase have been implicated in the progression of glomerulonephritis (GN). This study examined the effect of simultaneously interrupting Ang II and ROS with an Ang II receptor blocker (ARB), candesartan, and a free radical scavenger, probucol, in a model of progressive mesangioproliferative GN induced by the injection of anti-Thy-1 antibody into uninephrectomized rats. Nephritic rats were divided into four groups and given daily oral doses of the following: Vehicle, 1% probucol diet, 70 mg/L candesartan in drinking water, and probucol plus candesartan. These treatments lasted until day 56. Vehicle-treated nephritic rats developed progressively elevated proteinuria and glomerulosclerosis. Candesartan kept proteinuria significantly lower than vehicle or probucol. The addition of probucol to candesartan normalized urinary protein excretion. Increases in BP in nephritic rats were lowered by these treatments, except with probucol. It is interesting that both glomerular cell number and glomerulosclerosis were significantly decreased by candesartan and normalized by the addition of probucol. Immunohistochemical studies for TGF-beta1, collagen type I, and fibronectin revealed that the combined treatment abolished glomerular fibrotic findings compared with candesartan. In addition, glomerular expression of NADPH oxidase components and superoxide production suggested that the combined treatment completely eliminated NADPH oxidase-associated ROS production. In conclusion, our study provides the first evidence that the antioxidant probucol, when added to an Ang II receptor blockade, fully arrests proteinuria and disease progression in GN. Furthermore, the data suggest that NADPH oxidase-associated ROS production may play a pivotal role in the progression of GN. The combination of probucol and candesartan may represent a novel route of therapy for patients with progressive GN.
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PMID:Addition of the antioxidant probucol to angiotensin II type I receptor antagonist arrests progressive mesangioproliferative glomerulonephritis in the rat. 1646 49

We previously reported that reactive oxygen species (ROS) in paraventricular nucleus (PVN) modulated cardiac sympathetic afferent reflex (CSAR) and mediated the effect of angiotensin II (Ang II) in the PVN on the CSAR. In the present study, we investigated whether the NAD(P)H oxidase in the PVN was a key source of ROS which modulated the CSAR and contributed to the effect of Ang II on the CSAR. In anesthetized rats with sinoaortic denervation and vagotomy, renal sympathetic nerve activity (RSNA) and arterial pressure were recorded. The CSAR was evaluated by the RSNA response to epicardial application of bradykinin (BK). The NAD(P)H oxidase activity in the PVN was measured with lucigenin-enhanced chemiluminescent method. Microinjection of the NAD(P)H oxidase inhibitor, either apocynin (1.0 nmol) or phenylarsine oxide (PAO, 1.0 nmol), into the PVN significantly inhibited the CSAR. Microinjection of Ang II (0.3 nmol) into the PVN significantly augmented the CSAR. The effects of Ang II were not only abolished by pretreatment with either apocynin or PAO in the PVN but also partially inhibited by xanthine oxidase inhibitor allopurinol. Either epicardial application of BK or microinjection of Ang II into the PVN significantly increased NAD(P)H oxidase activity in the PVN. The effect of Ang II on NAD(P)H oxidase activity was abolished by pretreatment with AT(1) receptor antagonist losartan in the PVN. These findings suggested that NAD(P)H oxidase in the PVN was a major source of the ROS in modulating the CSAR, and the NAD(P)H oxidase contributes to the effect of Ang II on the CSAR.
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PMID:NAD(P)H oxidase in paraventricular nucleus contributes to the effect of angiotensin II on cardiac sympathetic afferent reflex. 1651 80

Angiotensin-converting enzyme inhibitors (ACE-Is) prevent target organ damage in several models of hypertension. The aim of this study was to assess the influence of the ACE-I enalapril (10 mg/kg(-1) per day, gavage) on the cardiovascular alterations and production of free radicals induced by chronic infusion of angiotensin II (Ang II, 200 ng/kg(-1) per minute, s.c.) in Sprague-Dawley rats. Enalapril was given concomitantly for the 10 days of Ang II infusion (prevention) or from day 10 to 17 of Ang II infusion (intervention). The influence of the NADPH oxidase inhibitor apocynin (600 mg/L(-1) in drinking water) was evaluated. Enalapril and apocynin had no effect on hypertension in the prevention and intervention studies. Enalapril prevented the increase in heart weight index (HWI), carotid cross-sectional area (CSA) and albuminuria induced by Ang II. Enalapril reduced HWI and albuminuria whereas CSA was not affected in the intervention study. Apocynin had effects comparable to enalapril. Both enalapril and apocynin reduced the overproduction of superoxide anion by the left ventricle and rise in advanced oxidation protein products induced by Ang II. Therefore, the antioxidant but not the antihypertensive effect of enalapril may participate in the prevention and treatment of the Ang II-induced cardiovascular and renal alterations.
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PMID:Prevention and reversal by enalapril of target organ damage in angiotensin II hypertension. 1652 47

Pathological and physiological hypertrophy of the heart is associated with decreased expression of the Kv4.3 transient outward current (Ito) channel. The downregulation of channel mRNA and protein, which may be proarrhythmic, is recapitulated with cultured neonatal rat ventricular myocytes treated with angiotensin II (Ang II). Here we show that the 4.9 kb 3' untranslated region (3' UTR) of the Kv4.3 channel transcript confers Ang II sensitivity to a promoter-reporter construct. In contrast, Kv4.2 and Kv1.5 3'-UTR sequences are insensitive to Ang II. Both Kv4.3 3'-UTR reporter mRNA and activity are decreased in Ang II-treated cardiac myocytes, in accordance with a decrease in mRNA stability. This regulation is mediated by Ang II type 1 (AT1) receptors and abolished by NADPH oxidase inhibitors and dominant negative rac. The Ang II effect is also blocked by expression of superoxide dismutase (SOD), but not catalase, showing that superoxide is required. Dominant negative subunits, enzyme inhibitors and hydrogen peroxide experiments show that the apoptosis signal-regulating kinase 1 (ASK1)-p38 kinase pathway mediates downstream signaling from NADPH oxidase. Mechanical stretch also downregulates Kv4.3 3'-UTR reporter activity and this requires AT1 receptors and NADPH oxidase. Thus, activation of AT1 receptors by Ang II or stretch specifically destabilizes cardiac myocyte Kv4.3 channel mRNA by activating NADPH oxidase. These results link long-term control of cardiac K+ channel gene expression to a physiological reactive oxygen species signaling pathway.
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PMID:Angiotensin II and stretch activate NADPH oxidase to destabilize cardiac Kv4.3 channel mRNA. 1655 64

A recent study documented reactive oxygen species (ROS), generated through NADPH oxidase by angiotensin II (Ang II) with the activation of NADPH oxidase subunits, p22phox and gp91phox, to be responsible for the preconditioning effect of Ang II. The present study was designed to determine if similar to ischemic preconditioning (PC), mitogen-activated protein (MAP) kinases are also involved in Ang II PC of the heart. Isolated working rat hearts were perfused for 15 min with KHB (Krebs-Henseleit bicarbonate) buffer containing Ang II in the absence or presence of an Erk (1/2) inhibitor, PD 098059, a p38MAPK inhibitor, SB 202190, a JNK inhibitor, SP 600125 or a ROS scavenger, N-acetyl cysteine (NAC). All hearts were subsequently subjected to 30 min global ischemia followed by 2 h reperfusion with KHB buffer only. Cardioprotection was examined by determining infarct size, cardiomyocyte apoptosis and ventricular recovery. Redox and MAP kinase regulation were studied by determining the survival signaling mediated by Akt and Bcl-2. In consistent with previous results, Ang II preconditioned the heart as evidenced by improved postischemic ventricular recovery and reduced infarct size and decreases cardiomyocyte apoptosis. Ang II phosphorylated both Akt, Bcl-2 and Bad, which was blocked by NAC, PD 098059 or SP 600125, but not by SB 202190. NAC, PD 098059 and SP600125, but not SB202190, also abolished the cardioprotective effect of Ang II preconditioning. The results indicate that Ang II preconditioning is potentiated through MAP kinases that are regulated by redox signaling.
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PMID:Redox regulation of angiotensin II preconditioning of the myocardium requires MAP kinase signaling. 2323 Jun 3

Calcium channel blockers have been shown to limit the progression of atherosclerosis and decrease the incidence of cardiovascular events. To investigate vasoprotective effects beyond the blood pressure-lowering effects of these agents, amlodipine (10(-6) mol/) and manidipine (10(-6) mol/l) were used to pretreat angiotensin (Ang) II-stimulated rat cultured aortic endothelial cells. A 3-h period of Ang II treatment enhanced superoxide generation and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase protein, as detected by dihydroethidium staining and Western blotting, respectively. Pretreatment with amlodipine or manidipine attenuated the increased production of superoxide and the overexpression of NADPH oxidase. The enhanced expression of heme oxygenase-1 (HO-1) mRNA induced by Ang II was further increased by amlodipine, whereas pretreatment with manidipine led to a reduction in the expression of HO-1. Furthermore, Ang II increased vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1) mRNA levels, as determined by reverse transcription (RT)-polymerase chain reaction (PCR). Pretreatment with either amlodipine or manidipine decreased the overexpression of VCAM-1, ICAM-1, and MCP-1. We also demonstrated that amlodipine or manidipine prevented the Ang II-induced increase in lectin-like oxidized low-density lipoprotein receptor1 (LOX-1) content, thereby restoring control levels. These observations showed that amlodipine and manidipine reduced superoxide generation by the inhibition of the overexpression of NADPH oxidase in Ang II-stimulated endothelial cells. Such antioxidant effects of these agents might in turn have led to a decrease in the expression of VCAM-1, ICAM-1 and MCP-1. The salutary effects of calcium channel blockers in atherogenesis include the inhibition of the expression of LOX-1.
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PMID:Calcium [corrected] channel blockers reduce angiotensin II-induced superoxide generation and inhibit lectin-like oxidized low-density lipoprotein receptor-1 expression in endothelial cells. 1675 44


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