UNIPROT:P04179 - FACTA Search

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Query: UNIPROT:P04179 (MnSOD)
2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To understand the basis of oligodendrocyte (OL) susceptibility to oxidative injury, purified rat OL cultures at different stages of maturation were exposed to nitric oxide (NO) donors with fast or slow kinetics of release and to tert-butyl-hydroperoxide, a membrane-permeant organic hydroperoxide. OL precursors (pre-OL) displayed the highest vulnerability to both oxygen or nitrogen reactive species, whereas mature OLs were uniquely vulnerable to long-lasting levels of NO. Cell death occurred by necrosis as well as apoptosis associated with increased caspase-3 activity and, only in the case of pre-OLs, with a decreased expression of the anti-apoptotic protein bcl-2. Pre-OLs were also more susceptible than mature OLs to lipid peroxidation, as measured by F2-isoprostane content in culture media. Finally, pre-OLs, but not mature OLs, expressed high levels of the mitochondrial scavenging enzyme Mn superoxide dismutase, suggesting that pre-OLs may efficiently convert anion superoxide into hydrogen peroxide and, paradoxically, be more predisposed than mature OLs to a toxic imbalance between hydrogen peroxide production and detoxification processes. These data suggest that susceptibility to lipid peroxidation, expression of the scavenging enzyme Mn superoxide dismutase and of the anti-apoptotic protein bcl-2, may contribute to the maturation-dependent vulnerability of OLs to oxidant injury.
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PMID:Differential lipid peroxidation, Mn superoxide, and bcl-2 expression contribute to the maturation-dependent vulnerability of oligodendrocytes to oxidative stress. 1276 90

Many individuals with cardiovascular diseases undergo physical conditioning with or without medication. Therefore, this study investigated the interaction of exercise training and chronic nitroglycerin treatment on blood pressure (BP) and changes in cardiac nitric oxide (NO) and antioxidants in rats. Fisher 344 rats were divided into four groups treated as: (1) sedentary control, (2) exercise training for 8 weeks, (3) nitroglycerin (15 mg/kg, s.c. for 8 weeks), and (4) training+nitroglycerin for 8 weeks. Respiratory exchange ratio (RER), BP, and heart rate (HR) were monitored weekly for 8 weeks. The animals were sacrificed 24 h after last treatments, hearts isolated, and analyzed. Physical conditioning significantly increased RER, cardiac NO levels, and endothelial eNOS protein expression. Training significantly enhanced cardiac glutathione (GSH) levels, GSH/GSSG ratio, and the up-regulation of cardiac copper/zinc-superoxide dismutase (CuZn-SOD), manganese (Mn)-SOD, catalase (CAT), glutathione peroxidase (GSH-Px) activities, and protein expression. Training also caused depletion of cardiac malondialdehyde (MDA) and protein carbonyls with a significant increase in RER without any change in BP and HR. Chronic nitroglycerin administration significantly increased cardiac NO levels and eNOS protein expression. Nitroglycerin administration significantly enhanced cardiac Mn-SOD, CAT, and GST activities, and protein expression with decreased MDA levels and BP. Interaction of training and chronic nitroglycerin treatment increased cardiac NO levels with enhanced eNOS and iNOS protein expressions, GSH/GSSG ratio, and the up-regulation of antioxidant enzymes. This interaction normalized BP and HR and increased RER. The data suggest that the interaction of physical training and chronic nitroglycerin treatment resulted in the maintenance of BP and RER by up-regulating the antioxidants and NO levels and by reducing the oxidative stress in the rat heart.
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PMID:Interaction of physical training and chronic nitroglycerin treatment on blood pressure, nitric oxide, and oxidants/antioxidants in the rat heart. 1286 Apr 43

Mitochondria are the major site for the generation of ATP at the expense of molecular oxygen. Significant fractions (approximately 2%) of oxygen are converted to the superoxide radical and its reactive metabolites (ROS) in and around mitochondria. Although ROS have been known to impair a wide variety of biological molecules including lipids, proteins and DNA, thereby causing various diseases, they also play critical roles in the maintenance of aerobic life. Because mitochondria are the major site of free radical generation, they are highly enriched with antioxidants including GSH and enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase, on both sides of their membranes to minimize oxidative stress in and around this organelle. The present work reviews the sites and mechanism of ROS generation by mitochondria, mitochondrial localization of Mn-SOD and Cu,Zn-SOD which has been postulated for a long time to be a cytosolic enzyme. The present work also describes that a cross-talk of molecular oxygen, nitric oxide (NO) and superoxide radicals regulates the circulation, energy metabolism, apoptosis, and functions as a major defense system against pathogens. Pathophysiological significance of ROS generation by mitochondria in the etiology of aging, cancer and degenerative neuronal diseases is also described.
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PMID:Mitochondrial generation of reactive oxygen species and its role in aerobic life. 1452 65

Differential expression and activity of constitutive mitochondrial nitric oxide synthase (mtNOS) in the mitochondrial compartment is followed by significant variations in matrix nitric oxide (NO) steady-state concentration. The mitochondrial utilization of NO involves the production of superoxide anion and H(2)O(2), a species freely diffusible outside the mitochondria that participates in the modulation of cell proliferation and apoptosis and in cell transformation and cancer. On these bases, we analyzed the modulation of mtNOS in the frame of cellular redox state in M3, MM3, and P07 murine tumors and their respective cell lines, as compared with normal proliferating and quiescent tissues. The results showed that: (a) tumoral and proliferating mitochondria only retain 10-50% of the activity of complexes I, II-III, and IV and Mn-SOD of quiescent tissues; (b) normal proliferating tissues, like embryonic liver or pregnant mammary gland, have 10-20% of mtNOS expression and activity and mitochondrial H(2)O(2) yield than quiescent nonproliferating tissues; (c) similarly but irrespective of mtNOS expression, tumoral mitochondria have no >5% of mtNOS activity and H(2)O(2) yield of mature tissues; and (d) in opposition to stable tissues, both tumoral and normal proliferating cells exhibit high cyclin D1 expression and low pro-apoptotic p38mitogen-activated protein kinase activity. Dually, H(2)O(2) stimulated tumor cell proliferation (<10 microM) or markedly inhibited it (>10 microM) with parallel variations of cyclin D1, phospho-extracellular-regulated kinase1/2, and phospho-p38mitogen-activated protein kinase. It is surmised that decreased oxidative phosphorylation, defective tumoral mtNOS, and low mitochondrial NO-dependent H(2)O(2) may be a platform to link persistent tumoral growth to embryonic behavior.
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PMID:Decreased mitochondrial nitric oxide synthase activity and hydrogen peroxide relate persistent tumoral proliferation to embryonic behavior. 1455 26

We have explored the impact of nitric oxide (NO) exposure on oxidation damage of lipids, and proteins, and the contribution of this type of damage to the activation of the apoptotic program in insulin secreting RINm5F cells. Exposure of cells to NO donors and to interleukin-1 beta (IL-1beta) led to generation of lipooxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Addition of superoxide dismutase (SOD) and catalase (Cat) to cells decreased by 50% MDA and 4-HNE production induced by IL-1beta. Over-expression of Mn-SOD in cells conferred a remarkable decrease (75%) in IL-1beta-induced lipid peroxidation. These data suggest that peroxynitrite (ONOO(-)) mediates peroxidative damage to lipids in this cell system. Inhibitors of advanced lipooxidation end products (ALEs) formation such as aminoguanidine (AG) and pyridoxamine (PM) prevented partially apoptotic events triggered by NO such as DNA fragmentation, caspase-3 activation and cytochrome c release from mitochondria. These findings indicate that ALEs are involved in NO-induced apoptosis. In fact, NO-induced carbonylation of PARP protein preceded its apoptotic degradation and inhibitors of ALEs formation prevented both events. We thus propose that carbonylation of proteins is instrumental in linking NO-dependent lipid oxidation and apoptosis in this cell system.
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PMID:Involvement of advanced lipooxidation end products (ALEs) and protein oxidation in the apoptotic actions of nitric oxide in insulin secreting RINm5F cells. 1459 54

Cortical spreading depression (CSD) is characterized by slowly propagating waves of neuronal/astrocytic depolarization and metabolic changes, followed by a period of quiescent neuronal and electroencephalographic activity. CSD acts as a preconditioning stimulus in brain, reducing cell death when elicited up to several days prior to an ischemic insult. Precise mechanisms associated with this neuroprotection are not known, although CSD increases the expression of a number of potentially neuroprotective genes/proteins. The nitric oxide (NO) system may be of particular importance, as it is acutely activated and chronically up-regulated in cerebral cortex by CSD, and NO can ameliorate and exacerbate cell death under different conditions. Several molecules have recently been identified that modulate the production and/or cellular actions of NO, but it is not known whether their expression is altered by CSD. Therefore, the present study examined the effect of CSD on the spatiotemporal expression of PIN, CAPON, PSD-95, Mn-SOD and Cu/Zn-SOD mRNA in the rat brain. In situ hybridization using specific [35S]-labelled oligonucleotides revealed that levels of PIN mRNA were significantly increased in the cortex and claustrum ( approximately 30-180%; p </= 0.01) after 6 h and 1 and 2 days, but were again equivalent to contralateral (control) cortical values at 7, 14 and 28 days. CAPON mRNA levels were increased ( approximately 30-180%; p </= 0.05) in the ipsilateral cortical hemisphere at 6 h and 2 days post treatment, but not at the other times examined. In contrast, levels of PSD-95, Mn- and Cu/Zn-SOD mRNA were not altered at any time after CSD. These results suggest that following CSD, nNOS activity and NO levels may be tightly regulated by both transcriptional and translational alterations in a range of nNOS adaptor proteins, which may contribute to CSD-induced neuroprotection against subsequent ischemia.
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PMID:Neuronal-NOS adaptor protein expression after spreading depression: implications for NO production and ischemic tolerance. 1471 93

Generation of high levels of nitric oxide (NO) following induction of NOS2 by interleukin-1 beta (IL-1beta) triggers beta cell apoptosis in insulin-secreting RINm5F cells. Mitochondrial and nuclear events such as downregulation of the antiapoptotic protein Bcl-2, activation of the pore responsible for the permeability transition (PT) and DNA fragmentation are involved in the process. We report in the present paper that exposure of insulin-producing RINm5F cells to NO donors and to IL-1beta leads to oxidative carbonylation of both Bcl-2 and the adenine nucleotide translocator (ANT) component of the mitochondrial PT pore. When the effect of endogenous generation of high concentrations of NO following exposure of cells to IL-1beta was studied, carbonylation of Bcl-2 preceded downregulation of the protein. Overexpression of Mn-SOD decreases substantially the extent of Bcl-2 carbonylation in SIN-1-exposed cells. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inhibition, carbonylation and translocation from cytoplasm to nucleus and DNA fragmentation were also induced by DETA/NO exposure. DETA/NO-induced carbonylation of Bcl-2 and ANT proteins takes place 6 h before apoptotic release of histone-associated DNA to cytoplasm. Time course studies also reveal a close parallel between GAPDH translocation to nucleus and carbonylation. Inhibitors of lipooxidation end products formation such as piridoxamine (PM) and aminoguanidine (AG) block NO-triggered carbonylation of Bcl-2, ANT and GAPDH, prevent NO-induced GAPDH enzyme inhibition and nuclear translocation and DNA fragmentation. Our results support the notion that the oxidative carbonylation of proteins plays a role in the control of NO-induced apoptosis.
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PMID:Nitric oxide-induced carbonylation of Bcl-2, GAPDH and ANT precedes apoptotic events in insulin-secreting RINm5F cells. 1472 54

Many cardiac patients undergo exercise conditioning with or without medication. Therefore, we investigated the interaction of exercise training and chronic nitroglycerin treatment on blood pressure (BP), aortic nitric oxide (NO), oxidants and antioxidants in rats. Fisher 344 rats were divided into four groups and treated as follows: (1) sedentary control, (2) exercise training (ET) for 8 weeks, (3) nitroglycerin (15 mg/kg, s.c. for 8 weeks) and (4) ET+nitroglycerin. BP was monitored with tail-cuff method. The animals were sacrificed 24 h after the last treatments and thoracic aorta was isolated and analyzed. Exercise training on treadmill for 8 weeks significantly increased respiratory exchange ratio (RER), aortic NO levels, and endothelial nitric oxide synthase (eNOS) protein expression. Training significantly enhanced aortic glutathione (GSH), reduced to oxidized glutathione (GSH/GSSG) ratio, copper/zinc-superoxide dismutase (CuZn-SOD), Mn-SOD, catalase (CAT), glutathione peroxidase (GSH-Px) glutathione disulfide reductase (GR) activities and protein expressions. Training significantly depleted aortic malondialdehyde (MDA) and protein carbonyls without change in BP. Nitroglycerin administration for 8 weeks significantly increased aortic NO levels and eNOS protein expression. Nitroglycerin significantly enhanced aortic Mn-SOD, CAT, GR and glutathione-S-transferase (GST) activities and protein expressions with decreased MDA levels, protein carbonyls and BP. Interaction of training and nitroglycerin treatment significantly increased aortic NO levels, eNOS protein expression, GSH/GSSG ratio, antioxidant enzymes and normalized BP. The data suggest that the interaction of training and nitroglycerin maintained BP by up-regulating the aortic NO and antioxidants and reducing the oxidative stress in rats.
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PMID:Interaction of regular exercise and chronic nitroglycerin treatment on blood pressure and rat aortic antioxidants. 1473 77

We hypothesized that aging is characterized by a reduced release of nitric oxide (NO) in response to shear stress in resistance vessels. Mesenteric arterioles and arteries of young (6 mo) and aged (24 mo) male Fischer 344 rats were isolated and cannulated. Shear stress (15 dyn/cm(2))-induced dilation was significantly reduced and shear stress (1, 5, 10, and 15 dyn/cm(2))-induced increases in perfusate nitrite were significantly smaller at all shear stress levels in vessels of aged rats. Inhibition of NO synthesis abolished shear stress-induced release of nitrite. Furthermore, shear stress (15 dyn/cm(2))-induced release of nitrate was significantly higher and total nitrite (nitrite plus nitrate) was significantly lower in vessels of aged rats. Tiron or SOD significantly increased nitrite released from vessels of aged rats, but this was still significantly less than that in young rats. Superoxide production was increased and the activity of SOD was decreased in vessels of aged rats. There were no differences in endothelial NO synthase (eNOS) protein and basal activity or in Cu/Zn-SOD and Mn-SOD proteins in vessels of the two groups, but extracellular SOD was significantly reduced in vessels of aged rats. Maximal release of NO induced by shear stress plus ACh (10(-5) M) was comparable in the two groups, but phospho-eNOS in response to shear stress (15 dyn/cm(2)) was significantly reduced in vessels of aged rats. These data suggest that an increased production of superoxide, a reduced activity of SOD, and an impaired shear stress-induced activation of eNOS are the causes of the decreased shear stress-induced release of NO in vessels of aged rats.
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PMID:Reduced release of nitric oxide to shear stress in mesenteric arteries of aged rats. 1475 61

This study was performed to investigate the role of reactive oxygen species and inducible nitric oxide (NO) synthase (iNOS) and cyclooxygenase-2 (COX-2) metabolites in the lipopolysaccharide effect on bradykinin-induced relaxation in middle cerebral arteries from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). LPS exposure (10 microg/ml for 1-5 h) reduced bradykinin relaxation; this effect appeared earlier and was greater in arteries from SHR than WKY rats. LPS also reduced the relaxation to the NO donor diethylamine (DEA)-NO; however, LPS modified neither the bradykinin relaxation after inhibiting NO synthesis with N(G)-monomethyl-L-arginine (0.1 mM) nor endothelial NOS expression. In arteries from WKY rats, the respective iNOS and COX-2 inhibitors aminoguanidine (0.1 mM) and NS-398 (10 microM) and the superoxide anion scavenger SOD (100 U/ml) reduced the LPS effect on bradykinin relaxation; however, the thromboxane A(2) (TxA(2))PGH(2) receptor antagonist SQ-29548 (1 microM) and the H(2)O(2) scavenger catalase (1,000 U/ml) did not modify the LPS effect. In arteries from SHR, all of these drugs reduced the LPS effect. LPS exposure (5 h) increased superoxide anion levels in arteries from both strains and TxA(2) levels only in SHR. COX-2 expression rose to a similar level in arteries from both strains after 1 and 5 h of LPS incubation, whereas expression of Cu/Zn- and Mn-SOD only increased after 5 h. In conclusion, in segments from WKY rats, LPS reduced bradykinin-induced relaxation through increased production of NO (from iNOS) and superoxide anion. The greater LPS effect observed in arteries from SHR seems to be related to higher participation of reactive oxygen species and contractile prostanoids (probably TxA(2)).
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PMID:Hypertension alters role of iNOS, COX-2, and oxidative stress in bradykinin relaxation impairment after LPS in rat cerebral arteries. 1500 39

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