Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutrophils are mobilized to the vascular wall during vessel inflammation. Published data are conflicting on phagocytic nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activation during the hypertensive state, and the capacity of angiotensin II (Ang II) to modulate the intracellular redox status has not been analyzed in neutrophils. We here describe that Ang II highly stimulates endogenous and extracellular O2- production in these cells, consistent with the translocation to the cell membrane of the cytosolic components of NADPH oxidase, p47phox, and p67phox. The Ang II-dependent O2- production was suppressed by specific inhibitors of AT1 receptors, of the p38MAPK and ERK1/2 pathways, and of flavin oxidases. Furthermore, Ang II induced a robust phosphorylation of p38MAPK, ERK1/2, and JNK1/2 (particularly JNK2), which was hindered by inhibitors of NADPH oxidase, tyrosine kinases, and ROS scavengers. Ang II increased cytosolic Ca2+ levels-released mainly from calcium stores-enhanced the synthesis de novo and activity of calcineurin, and stimulated the DNA-binding activity of the transcription factor NF-kappaB in cultured human neutrophils. Present data demonstrate for the first time a stimulatory role of Ang II in the activation of phagocytic cells, underscore the relevant role of ROS as mediators in this process, and uncover a variety of signaling pathways by which Ang II operates in human neutrophils.
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PMID:Oxidative stress is a critical mediator of the angiotensin II signal in human neutrophils: involvement of mitogen-activated protein kinase, calcineurin, and the transcription factor NF-kappaB. 1266 41

A multitude of studies in experimental animals, together with clinical data, provide evidence that increased production of ROS (reactive oxygen species) are involved in the development and progression of cardiovascular disease. As ROS appear to have a critical role in atherosclerosis, there has been considerable interest in identifying the enzyme systems involved and in developing strategies to reduce oxidative stress. Prospective clinical trials with vitamins and hormone replacement therapy have not fulfilled earlier promises, although there is still interest in other dietary supplements. Superoxide dismutase mimetics, thiols, xanthine oxidase and NAD(P)H oxidase inhibitors are currently receiving much interest, while animal studies using gene therapy show promise, but are still at an early stage. Of the drugs in common clinical use, there is evidence that ACE (angiotensin-converting enzyme) inhibitors and AT1 (angiotensin II type 1) receptor blockers have beneficial effects on oxidative stress above their antihypertensive properties, whereas statins, in addition to improving lipid profiles, may also lower oxidative stress.
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PMID:Strategies to reduce oxidative stress in cardiovascular disease. 1473 10

Three water-soluble carboxy nitroxide antioxidants, 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl, 4-carboxy-2,2,6,6-tetramethylpiperidin-1-yloxyl, and 3-carboxy-2,2,5,5-tetramethylpyrrolidin-1-yloxyl, show significant impact on the postirradiation survival rates of ataxia telangiectasia (A-T) cells compared to normal cells, an assay which represents a model for understanding the impact of ROS damage on the A-T phenotype. The effects of these antioxidants are much more significant than those of vitamin E or Trolox (a water-soluble vitamin E analog), studied using the same cell survival model.
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PMID:The impact of carboxy nitroxide antioxidants on irradiated ataxia telangiectasia cells. 1533 10

Angiotensin II, a profibrotic cytokine, plays a main role in the initiation of renal fibrogenesis at a very early stage leading to a progressive loss of renal function in unilateral ureteral obstruction (UUO). We studied the involvement of AT1 angiotensin II receptor in the physiopathology of tubulointerstitial fibrosis in UUO, focusing in the regulation of the oxidative stress state and in the HSP 70 expression, in renal tissue. UUO or control sham operation was perform to Wistar Kyoto rats after being treated with the AT1 angiotensin II receptor antagonist Losartan (10 mg/kg/day) in the drinking water for 15 days. Twenty four hours later, mRNA AT1 receptor expression was studied. Renal fibrosis was evaluated through TGFbeta expression and superoxide dismutase (SOD) activity, hydroxyl radicals, O2- and total antioxidant activity were measured by spectrophotometric assay. Immunohistochemical and Western blot analysis of HSP 70 were performed. A non-hypotensive dose of Losartan significantly down regulated the expression of AT1 receptor. Prevention of renal fibrogenesis by Losartan treatment was demonstrated by TGFbeta mRNA expression similar to control. Oxidative stress in obstructed kidney was evident since a decreased SOD activity and a two-fold increase in the concentration of hydroxyl radicals and O2- was observed when compared to the control. Losartan produced down regulation of ROS with recovery of the SOD activity and higher expression of HSP 70 compared to obstructed kidney of rats receiving vehicle. We can conclude that after 24 hr of UUO, protection against tubulointerstitial fibrosis by Losartan, independent from changes in blood pressure, includes decreased oxidative stress linked to upregulation of HSP 70 expression.
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PMID:Angiotensin II type I antagonist on oxidative stress and heat shock protein 70 (HSP 70) expression in obstructive nephropathy. 1630 79

The renin-angiotensin system (RAS) is important for regulating blood pressure and extracellular fluid. The concept of the RAS has recently evolved from a classical systemic endocrine system to an appreciation of local RASs functioning in a paracrine manner, including in the vascular wall. Angiotensin II (AII), the main effector of the RAS, is a potent vasoconstrictor formed by the action of angiotensin-converting enzyme (ACE). ACE is multifunctional and also destroys the endogenous vasodilator bradykinin. A recently discovered novel ACE2 enzyme is responsible for forming a vasodilatory compound, angiotensin 1-7, from AII. Thus, the actions of ACE and ACE2 are antagonistic. Tissue actions of AII are mediated by specific receptors, AT1 and AT2, with AT1 mediating the classical actions. AT1-stimulated vasoconstricton occurs via phospholipase-D-mediated second messenger generation directly, and indirectly via the coupling of AT1 to the prooxidant enzyme NADPH oxidase. Since the vascular NADPH oxidase is a major source of vascular reactive oxygen species generation and is responsible for the breakdown of the vasodilator nitric oxide (NO), there is another potential link between RAS and regulation of vasodilatory pathways. AT2 signaling is antagonistic to AT1 signaling, and results in bradykinin and NO formation. Chronic AII signaling induces vascular dysfunction, whereas pharmacological management of the RAS can not only control blood pressure, but also correct endothelial dysfunction in hypertensives. Exercise training can also improve endothelial function in hypertensives, raising the question of whether there is a potential role for RAS in mediating the vascular effects of exercise training. Recent studies have demonstrated reductions in the expression of NADPH oxidase components in the vascular wall in response to exercise training, thus tempering one of the main cellular effectors of AII, and this is associated with reduced vascular ROS production and enhanced NO bioavailability. Importantly, it has now been demonstrated in human arteries that exercise training also tempers vascular AT1 receptor expression and AII-induced vasoconstriction, while enhancing endothelium-dependent dilation. The signals responsible for these chronic adaptations are not clearly understood, and may include changes in RAS components prompted by acute exercise. ACE genotype may have an effect on physical activity levels and on the cardiovascular responses to exercise training, and the II genotype (compared with ID and DD) is associated with the largest endothelium-dependent dilations in athletes compared with those in sedentary individuals. Thus, the tissue location of the RAS, the complement of ACE/ACE2, the receptor expression of AT1/AT2, and the ACE genotype are all variables that could impact the vascular responses to exercise training, but the responses of most of these variables to regular exercise training and the mechanisms responsible have not been systematically studied.
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PMID:Vascular biology of angiotensin and the impact of physical activity. 1834 68

Angiotensin II (Ang II) not only mediates the effects of vasoconstriction and blood pressure regulation, but is also implicated in inflammation, endothelial dysfunction, atherosclerosis, hypertension and congestive heart failure. Ang 1I activates pathways of MAPK, NADPH and ROS, non-receptor tyrosine kinases and receptor tyrosine kinases via AT1 receptor to produce various effects involved in regulation of endothelial functions, endothelial dysfunction and vascular inflammation response.
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PMID:[Progress in signal transduction pathways mediating effects of angiotensin II in endothelial cells]. 1881 91

Cellular senescence is a stress-response phenomenon in which cells lose the ability to proliferate; it is induced by telomere shortening, activation of oncogenes or tumor suppressor genes, or exposure to a sub-lethal dose of DNA damaging agents or oxidative stresses. cDNA microarray analysis reveals that the levels of interferons (IFNs) and IFN-inducible genes were altered during replicative senescence in human umbilical vascular endothelial cells (HUVECs). However, the role of IFNs in cellular senescence of HUVECs remains unidentified. This study demonstrated that prolonged treatment with IFN-gamma induced cellular senescence in HUVECs, as confirmed by G0/G1 cell cycle arrest, up-regulation of p53 and p21 protein levels, increased SA-beta-gal staining, and the accumulation of phospho-H(2)AX foci. IFN-gamma-induced cellular senescence was observed only in p16-knockdown cells or p16-null mouse embryonic fibroblasts (MEFs), but not in p53-knockdown cells or p53-null MEFs. IFN-gamma treatment increased ROS production, and an antioxidant, N-acetylcysteine, inhibited IFN-gamma-induced cellular senescence. Knockdown of ATM kinase or IFI16 rescued IFN-gamma-induced cellular senescence. Therefore, these results suggest that IFN-gamma might play an important role in cellular senescence through a p53-dependent DNA damage pathway and contribute to the pathogenesis of atherosclerosis via its pro-senescent activity.
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PMID:Interferon-gamma induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells. 1907 Nov 56

We describe the events triggered by a sub-lethal concentration of airborne particulate matter (PM(10)) in A549 cells, which include the formation DNA double-strand breaks, gammaH2A.X generation, and 53BP1 recruitment. To protect the genome, cells activated ATM/ATR/Chk1/Chk2/p53 pathway but, after 48 h, cells turned into a senescence-like state. Trolox, an antioxidant, was able to prevent most of the alterations observed after particulate matter exposure, demonstrating the important role of ROS as mediator of PM(10)-induced genotoxicity and suggesting that DNA damage could be the mechanisms by which particulate matter augment the risk of lung cancer.
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PMID:DNA damage response of A549 cells treated with particulate matter (PM10) of urban air pollutants. 1921 10

Ionizing radiation can induce genomic instability in the progeny of irradiated cells, as was demonstrated in various experimental systems. Most in vitro studies have utilized replicating cells, but it is not clear whether radiation-induced genomic instability persists in quiescent cells. Here we show the induction of X-ray-induced genomic instability in normal human diploid cells irradiated and maintained in a quiescent state for up to 24 months while cells were subcultured approximately once every 2-3 months. Every 12 months, a fraction of the irradiated cell population was stimulated to divide by culturing at a low density, and we found that these cells showed increased frequencies of phosphorylated ATM foci, decreased colony-forming ability, and increased frequency of chromosomal aberrations. No significant increases in ROS levels were detected in long-term cultured cells. These results suggest that there are ROS-independent mechanism(s) induced by radiation, which can generate persistent delayed effects in quiescent cells, and could ultimately contribute to carcinogenesis.
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PMID:Long-term persistence of X-ray-induced genomic instability in quiescent normal human diploid cells. 1971 88

The p400 E1A-associated protein, which mediates H2A.Z incorporation at specific promoters, plays a major role in cell fate decisions: it promotes cell cycle progression and inhibits induction of apoptosis or senescence. Here, we show that p400 expression is required for the correct control of ROS metabolism. Depletion of p400 indeed increases intracellular ROS levels and causes the appearance of DNA damage, indicating that p400 maintains oxidative stress below a threshold at which DNA damages occur. Suppression of the DNA damage response using a siRNA against ATM inhibits the effects of p400 on cell cycle progression, apoptosis, or senescence, demonstrating the importance of ATM-dependent DDR pathways in cell fates control by p400. Finally, we show that these effects of p400 are dependent on direct transcriptional regulation of specific promoters and may also involve a positive feedback loop between oxidative stress and DNA breaks since we found that persistent DNA breaks are sufficient to increase ROS levels. Altogether, our results uncover an unexpected link between p400 and ROS metabolism and allow deciphering the molecular mechanisms largely responsible for cell proliferation control by p400.
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PMID:The E1A-associated p400 protein modulates cell fate decisions by the regulation of ROS homeostasis. 2054 51


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