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)

Insulin resistance and oxidative stress act synergistically in the development of cardiovascular complications. The present study compared the efficacy of three polyphenolic extracts in their capacity to prevent hypertension, cardiac hypertrophy, increased production of reactive oxygen species (ROS) by the aorta or the heart, and increased expression of cardiac NAD(P)H oxidase in a model of insulin resistance. Rats were fed a 60%-enriched fructose food and were treated once a day (gavage) for 6 weeks with 10 mL/kg of water only (F group) or the same amount of solution containing a red grape skin polyphenolic extract enriched in anthocyanins (ANT), a grape seed extract enriched in procyanidins and rich in galloylated procyanidins (PRO), or the commercial preparation Vitaflavan (VIT), rich in catechin oligomers. All treatments were administered at the same dose of 21 mg/kg of polyphenols. Our data indicate that (a) the ANT treatment prevented hypertension, cardiac hypertrophy, and production of ROS, (b) the PRO treatment prevented insulin resistance, hypertriglyceridemia, and overproduction of ROS but had only minor effects on hypertension or hypertrophy, while (c) Vitaflavan prevented hypertension, cardiac hypertrophy, and overproduction of ROS. All polyphenolic treatments prevented the increased expression of the p91phox NADPH oxidase subunit. In summary, our study suggest that (a) the pathogeny of cardiac hypertrophy in the fructose-fed rat disease involves both hypertension and hyperproduction of ROS, (b) polyphenolic extracts enriched in different types of polyphenols possess differential effects on insulin resistance, hypertension, and cardiac hypertrophy, and (c) polyphenols modulate the expression of NAD(P)H oxidase.
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PMID:Extracts enriched in different polyphenolic families normalize increased cardiac NADPH oxidase expression while having differential effects on insulin resistance, hypertension, and cardiac hypertrophy in high-fructose-fed rats. 1563 22

In diabetes and insulin resistance, activation of protein kinase C (PKC) in vascular cells may be a key link between elevated plasma and tissue concentrations of glucose and nonesterified fatty acids and abnormal vascular cell signaling. Initial studies of PKC activation in diabetes focused on microvascular complications, but increasing evidence supports that PKC plays a role in several mechanisms promoting atherosclerosis. This review explains how PKC is thought to be activated in diabetes and insulin resistance through de novo synthesis of diacylglycerol. Furthermore, the review summarizes studies that implicate PKC in promoting proatherogenic mechanisms or inhibiting antiatherogenic mechanisms, including studies of endothelial dysfunction; gene induction and activation of vascular NAD(P)H oxidase; endothelial nitric oxide synthase expression and function; endothelin-1 expression; growth, migration, and apoptosis of vascular smooth muscle cells; induction of adhesion molecules; and oxidized low-density lipoprotein uptake by monocyte-derived macrophages.
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PMID:Proatherosclerotic mechanisms involving protein kinase C in diabetes and insulin resistance. 1563 6

Insulin resistance (IR) and associated hyperinsulinemia are major risk factors for coronary artery disease. Mechanisms linking hyperinsulinemia to coronary vascular dysfunction in IR are unclear. We evaluated insulin-induced vasodilation in isolated small coronary arteries (SCA; approximately 225 microm) of Zucker obese (ZO) and control Zucker lean (ZL) rats. Vascular responses to insulin (0.1-100 ng/ml), ACh (10(-9)-10(-5) mol/l), and sodium nitroprusside (10(-8)-10(-4) mol/l) were assessed in SCA by measurement of intraluminal diameter using videomicroscopy. Insulin-induced dilation was decreased in ZO compared with ZL rats, whereas ACh and sodium nitroprusside elicited similar vasodilations. Pretreatment of arteries with SOD (200 U/ml), a scavenger of reactive oxygen species (ROS), restored the vasorelaxation response to insulin in ZO arteries, whereas ZL arteries were unaffected. Pretreatment of SCA with N-nitro-L-arginine methyl ester (100 micromol/l), an inhibitor of endothelial nitric oxide (NO) synthase (eNOS), elicited a vasoconstrictor response to insulin that was greater in ZO than in ZL rats. This vasoconstrictor response was reversed to vasodilation in ZO and ZL rats by cotreatment of the SCA with SOD or apocynin (10 micromol/l), a specific inhibitor of vascular NADPH oxidase. Lucigenin-enhanced chemiluminescence showed increased basal ROS levels as well as insulin (330 ng/ml)-stimulated production of ROS in ZO arteries that was sensitive to inhibition by apocynin. Western blot analysis revealed increased eNOS expression in ZO rats, whereas Mn SOD and Cu,Zn SOD expression were similar to ZL rats. Thus IR in ZO rats leads to decreased insulin-induced vasodilation, probably as a result of increased production of ROS by vascular NADPH oxidase, leading to decreased NO bioavailability, despite a compensatory increase in eNOS expression.
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PMID:Impaired insulin-induced vasodilation in small coronary arteries of Zucker obese rats is mediated by reactive oxygen species. 1565 Jan 57

Propelled by the identification of a small family of NADPH oxidase (Nox) enzyme homologs that produce superoxide in response to cellular stimulation with various growth factors, renewed interest has been generated in characterizing the signaling effects of reactive oxygen species (ROS) in relation to insulin action. Two key observations made >30 years ago-that oxidants can facilitate or mimic insulin action and that H(2)O(2) is generated in response to insulin stimulation of its target cells-have led to the hypothesis that ROS may serve as second messengers in the insulin action cascade. Specific molecular targets of insulin-induced ROS include enzymes whose signaling activity is modified via oxidative biochemical reactions, leading to enhanced insulin signal transduction. These positive responses to cellular ROS may seem "paradoxical" because chronic exposure to relatively high levels of ROS have also been associated with functional beta-cell impairment and the chronic complications of diabetes. The best-characterized molecular targets of ROS are the protein-tyrosine phosphatases (PTPs) because these important signaling enzymes require a reduced form of a critical cysteine residue for catalytic activity. PTPs normally serve as negative regulators of insulin action via the dephosphorylation of the insulin receptor and its tyrosine-phosphorylated cellular substrates. However, ROS can rapidly oxidize the catalytic cysteine of target PTPs, effectively blocking their enzyme activity and reversing their inhibitory effect on insulin signaling. Among the cloned Nox homologs, we have recently provided evidence that Nox4 may mediate the insulin-stimulated generation of cellular ROS and is coupled to insulin action via the oxidative inhibition of PTP1B, a PTP known to be a major regulator of the insulin signaling cascade. Further characterization of the molecular components of this novel signaling cascade, including the mechanism of ROS generated by insulin and the identification of various oxidation-sensitive signaling targets in insulin-sensitive cells, may provide a novel means of facilitating insulin action in states of insulin resistance.
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PMID:Redox paradox: insulin action is facilitated by insulin-stimulated reactive oxygen species with multiple potential signaling targets. 1567 87

High glucose activates a myriad of signaling and gene expression pathways in non-insulin-dependent target cells causing diabetes complications. One of the earliest responses to high glucose by vascular cells is the generation of reactive oxygen species (ROS) that act directly on intracellular proteins and DNA, or indirectly as second messengers, transforming these cells into disease phenotypes. ROS are produced by mitochondria and/or NADPH oxidase in all target cells exposed to high glucose studied to date. Reports using cell cultures and diabetic animal models indicate that inhibition of ROS generation prevents the amplification of signaling and gene expression that are implicated in vascular complications. These models convincingly demonstrate that maneuvers preventing ROS production attenuate or completely abrogate early micro- and macrovascular end-organ damage of diabetes, including nephropathy, retinopathy, and large-vessel atherosclerosis. Attention now turns to the development of more effective antioxidants that could be used in clinical trials in the prevention and treatment of diabetes complications.
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PMID:Cellular mechanisms and treatment of diabetes vascular complications converge on reactive oxygen species. 1574 41

In diabetes mellitus (DM), the circulating renin-angiotensin system (RAS) is suppressed, but the renal tissue RAS is activated. Hyperglycemia increases tissue angiotensin II (Ang II), which induces oxidative stress, endothelial damage and disease pathology including vasoconstriction, thrombosis, inflammation and vascular remodeling. In early DM, the type 1 Ang II (AT(1)) receptor is upregulated but the type 2 Ang II (AT(2)) receptor is downregulated. This imbalance can predispose the individual to tissue damage. Hyperglycemia also increases the production of aldosterone, which has an unknown contribution to tissue damage. The insulin resistance state is associated with upregulation of the AT(1) receptor and an increase in oxygen free radicals in endothelial tissue caused by activation of NAD(P)H oxidase. Treatment with an AT(1) receptor blocker normalizes oxidase activity and improves endothelial function. An understanding of the tissue renin-angiotensin-aldosterone system, which is a crucial factor in the progression of tissue damage in DM, is imperative for protection against tissue damage in this chronic disease.
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PMID:The renin-angiotensin-aldosterone system, glucose metabolism and diabetes. 1580 10

Insulin resistance and central obesity are often associated with hypertension. The metabolic syndrome is a cluster of these common clinical disorders, and is related with an increased risk for cardiovascular diseases. A number of pro-inflammatory cytokines derived from adipose tissues have been thought to contribute to the development of insulin resistance and accelerated atherosclerosis. Among them, TNF-alpha has been most widely studied; it not only suppresses the insulin signaling, but also elicits vascular inflammation. Indeed, inhibition of TNF-alpha was found to improve insulin resistance in obese rats and reduce the progression of atherosclerosis in apolipoprotein E knockout mice, respectively. These observations demonstrate that TNF-alpha could play a central role in the pathogenesis of insulin resistance and accelerated atherosclerosis in the metabolic syndrome. Considering that the primary goals of treatment for hypertensive patients with the metabolic syndrome are prevention of the development of diabetes and cardiovascular events, anti-hypertensive drugs that have abilities to block the TNF-alpha signaling would be desirable as a first-line therapy for these patients. In the process of the search for such a unique anti-hypertensive drug, we have recently found that azelnidipine, a newly developed and commercially used long-acting dihydropyridine-based calcium antagonist (DHP), inhibited TNF-alpha-induced activator protein-1 activation and interleukin-8 expression in human umbilical vein endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation. The concentration of azelnidipine that was found effective in these in vitro-experiments is well within the therapeutic range. Since endothelial cells do not possess voltage-operated L-type calcium channels, these observations suggest that the beneficial effects of azelnidipine are not likely due to calcium channel blocking property, but due to its unique anti-oxidative ability. Furthermore, we have very recently found that serum levels of monocyte chemoattractant protein-1, a biomarker for subclinical atherosclerosis, were significantly decreased by the treatment of azelnidipine in patients with essential hypertension. In this paper, we would like to hypothesize that due to its unique TNF-alpha signal modulatory, anti-oxidative property, azelnidipine may be a promising DHP that targets diabetes and cardiovascular diseases in hypertensive patients with the metabolic syndrome.
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PMID:Unique atheroprotective property of azelnidipine, a dihydropyridine-based calcium antagonist. 1589 34

This study was undertaken to reveal the role of NAD(P)H oxidase in increased oxidative stress in islets of Type 2 diabetes. Immunostaining analysis showed that staining intensities of NAD(P)H oxidase components, gp91phox and p22phox, significantly increased in islets of animal models of Type 2 diabetes, OLETF rats (60 weeks of age) and db/db mice (14 weeks of age), compared with age-matched controls, respectively, correlating with increased levels of oxidative stress marker, 8-hydroxy-deoxyguanosine or 4-hydroxy-2-nonenal modified protein. In db/db mice, oral administration of angiotensin II Type 1 receptor antagonist valsartan (5 mg/kg) for 4 weeks significantly attenuated the increased expression of gp91phox and p22phox together with inhibition of oxidative stress and partially restored decreased insulin contents in islets. Angiotensin II-related increased expression of NAD(P)H oxidase may play an important role in increased oxidative stress in islets of Type 2 diabetes. This mechanism may be a novel therapeutic target for preventing beta-cell damage.
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PMID:Increased expression of NAD(P)H oxidase in islets of animal models of Type 2 diabetes and its improvement by an AT1 receptor antagonist. 1592 95

Hydrogen peroxide (H2O2) mimics many physiological responses of insulin, and increased H2O2 generation via the Nox-4 subunit of NAD(P)H oxidase was recently demonstrated to serve as a critical early step in the insulin signaling pathway. Exogenously added H2O2 has also been shown to activate several key components of the insulin signaling cascade. H2O2-induced signaling responses have been found to be associated with the activation of receptor and nonreceptor protein tyrosine kinases (PTK), including the insulin receptor (IR)-beta subunit. Therefore, in the present studies on Chinese hamster ovary cells overexpressing wild-type IR-PTK (CHO-IR) or a PTK-inactive form of IR (CHO-1018), we investigated whether IR-PTK plays a role in H2O2-induced signaling events. Treatment of CHO-IR cells with H2O2 increased the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), protein kinase B (PKB), and glycogen synthase kinase-3beta while enhancing tyrosine phosphorylation of the IR-beta subunit and the p85 subunit of phosphatidylinositol 3-kinase (PI3K). Compared with CHO-IR cells, the stimulatory effect of H2O2 on ERK1/2 and PKB was partially reduced in CHO-1018 cells. However, pharmacological inhibition of Src family PTK by 4-amino-5-(4-chlorophenyl)-7-(tert-butyl)pyrazolo[3,4-d]pyrimidine (PP-2) almost completely blocked H2O2-stimulated phosphorylation of the p85 subunit of PI3K, ERK1/2, and PKB. Moreover, H2O2, but not insulin, induced Tyr-418 phosphorylation of Src, which was also suppressed by PP-2. Taken together, these data suggest that both IR-PTK and Src family PTKs contribute to H2O2-induced signaling in CHO-IR cells albeit IR-PTK has a less dominant role in this process.
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PMID:H2O2-induced phosphorylation of ERK1/2 and PKB requires tyrosine kinase activity of insulin receptor and c-Src. 1599 56

Oxidants, including hydrogen peroxide (H2O2), have been recognized for years to mimic insulin action on glucose transport in adipose cells. Early studies also demonstrated the complementary finding that H2O2 was elaborated during treatment of cells with insulin, suggesting that cellular H2O2 generation was integral to insulin signaling. Recently, reactive oxygen species elicited by various hormones and growth factors have been shown to affect signal transduction pathways in various cell types. We recently reported that insulin-stimulated H2O2 modulates proximal and distal insulin signaling, at least in part through the oxidative inhibition of protein tyrosine phosphatases (PTPases) that negatively regulate the insulin action pathway. Nox4, a homologue in the family of NADPH oxidase catalytic subunits, was found to be prominently expressed in insulin-sensitive cells. By various molecular approaches, Nox4 was shown to mediate insulin-stimulated H2O2 generation and impact the insulin signaling cascade. Overexpression of Nox4 also significantly reversed the inhibition of insulin-stimulated receptor tyrosine phosphorylation by PTP1B, a widely expressed PTPase implicated in the negative regulation of insulin signaling, by inhibiting its catalytic activity. These recent studies have provided insight into Nox4 as a novel molecular link between insulin-stimulated reactive oxygen species and mechanisms involved in their modulation of insulin signal transduction.
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PMID:Role of insulin-induced reactive oxygen species in the insulin signaling pathway. 1599 57


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