The regulatory role of nitric oxide in apoptosis

Kim, Peter K.M.; Zamora, Rubén; Petrosko, Patricia; Billiar, Timothy R.

doi:10.1016/s1567-5769(01)00088-1

Cited by 358 publications

(251 citation statements)

References 206 publications

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“…These findings suggest that increased expression of iNOS in diabetic embryos results in an excess of nitric oxide, which then leads to peroxynitrite accumulation. Peroxynitrite is known to cause DNA damage, protein lipid peroxidation and protein degradation [22,41]. Thus, the present study suggests that the accumulation of peroxynitrite causes apoptosis during organogenesis, resulting in NTDs.…”

Section: Discussionmentioning

confidence: 53%

“…As expected, therefore, we detected elevated nitric oxide levels in E9.5 embryos of diabetic mice compared with those in non-diabetic mice. Although nitric oxide is a weak free radical, its oxidant properties are enhanced when nitric oxide reacts with a superoxide to form peroxynitrite [22]. Jawerbaum et al reported that intense nitrotyrosine immunostaining indicative of peroxynitrite was detected in the neural tube and neural folds of embryos of diabetic rats [23].…”

Section: Discussionmentioning

confidence: 99%

“…Such overproduction has been shown to exert an apoptotic effect in a variety of cells and is implicated in the pathogenesis of many disorders, including diabetic complications [20,21]. Nitric oxide reacts with superoxide to form the powerful oxidant, peroxynitrite (ONOO − ), which is thought to play a role in nitric oxidedependent cytotoxicity [22]. It has been reported that NOS activity and nitric oxide levels are elevated and that peroxynitrite is formed in the maldeveloped neural tube of embryos of diabetic dams [23].…”

Section: Introductionmentioning

confidence: 99%

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Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

et al. 2009

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Aims/hypothesis Maternal diabetes during pregnancy increases the risk of congenital malformations such as neural tube defects (NTDs). Although the mechanism of this effect is uncertain, it is known that levels of nitric oxide synthase (NOS) and nitric oxide are elevated in embryos of a mouse model of diabetes. We postulated that overproduction of nitric oxide causes diabetes-induced congenital malformations and that inhibition of inducible NOS (iNOS) might prevent diabetic embryopathy. Methods Mice were rendered hyperglycaemic by intraperitoneal injection of streptozotocin. The incidence of congenital malformations including NTDs was evaluated on gestational day 18.5. We assessed the involvement of iNOS in diabetesinduced malformation by administering ONO-1714, a specific inhibitor of iNOS, to pregnant mice with streptozotocininduced diabetic mice and by screening mice with iNOS deficiency due to genetic knockout (iNos −/− ). Results ONO-1714 markedly reduced the incidence of congenital anomalies, including NTDs, in fetuses of a mouse model of diabetes. It also prevented apoptosis in the head region of fetuses, indicating that iNOS is involved in diabetesrelated congenital malformations. Indeed, no NTDs were observed in fetuses of diabetic iNos −/− mice and the incidence of other malformations was also markedly reduced. Conclusions/interpretation We conclude that increased iNOS activity during organogenesis plays a crucial role in the pathogenesis of diabetes-induced malformations and suggest that inhibitors of iNOS might help prevent malformations, especially NTDs, in diabetic pregnancy.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

et al. 2009

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“…18,19 There is increasing evidence that alterations in NO production affect signal transduction pathways that control apoptotic cell Samples of lysates from cells incubated as described were subjected to LDS-PAGE and immunoblotting followed by densitometry to quantify PARP protein levels, which is reported relative to the density of the 116-kDa band at zero time ¼ 1.0, or were assayed for caspase-3 activity, which is reported relative to that of untreated cells at zero time ¼ 1.0. Results shown were replicated in two independent experiments…”

Section: Discussionmentioning

confidence: 99%

“…16,17 NO can have either pro-or antiapoptotic effects in different types of cells, dependent on its concentration and the overall oxidative status of the cell, among other factors. [18][19][20] Antiapoptotic effects of NO have been attributed to its ability to inhibit the caspase cascade via reversible S-nitrosylation of key cysteine residues in various caspases. [20][21][22][23][24] Thus, eNOS-synthesized NO inhibited caspase-mediated apoptosis in endothelial cells; 23 it has been speculated that diminished production or availability of NO and enhanced apoptosis is related to susceptibility to atherosclerosis or age-related endothelial dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Effect of staurosporine-induced apoptosis on endothelial nitric oxide synthase in transfected COS-7 cells and primary endothelial cells

2005

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Nitric oxide (NO) may block apoptosis by inhibiting caspases via S-nitrosylation of cysteines. Here, we investigated whether effector caspases might cleave and thereby inhibit endothelial nitric oxide synthase (eNOS). Exposure of eNOS-transfected COS-7 cells and bovine aortic endothelial cells to staurosporine resulted in significant loss of 135-kDa eNOS protein and activity, and appearance of a 60-kDa eNOS fragment; effects were inhibited by the general caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp[OMe]-fluoromethyl ketone (zVAD-fmk). In eNOS-transfected COS-7 cells, staurosporine-induced activation of caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage coincided with increased eNOS degradation and decreased activity. Loss of eNOS activity was greater than the degree of proteolysis. Incubation of immunoprecipitated eNOS with caspase-3, caspase-6 or caspase-7 resulted in eNOS cleavage. Staurosporine, a general protein kinase inhibitor, also reduced phosphorylation and decreased calmodulin binding, an effect that may explain the reduction in activity. eNOS, therefore, is both an inhibitor of apoptosis and a target of apoptosis-associated proteolysis.

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Stickstoffdioxid [MAK Value Documentation in German language, 2003]

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Gesundheitsschädliche Arbeitsstoffe , 37. Lieferung, Ausgabe 2003 Der Artikel enthält folgende Kapitel: Allgemeiner Wirkungscharakter Wirkungsmechanismus Toxikokinetik und Metabolismus Erfahrungen beim Menschen Einmalige Exposition Wiederholte Exposition Wirkung auf Haut und Schleimhäute Allergene Wirkung Reproduktionstoxizität Genotoxizität Kanzerogenität Tierexperimentelle Befunde und In‐vitro‐Untersuchungen Akute Toxizität Subakute, subchronische und chronische Toxizität Wirkung auf Haut und Schleimhäute Allergene Wirkung Reproduktionstoxizität Genotoxizität Kanzerogenität Bewertung

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The regulatory role of nitric oxide in apoptosis

Cited by 358 publications

References 206 publications

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

Effect of staurosporine-induced apoptosis on endothelial nitric oxide synthase in transfected COS-7 cells and primary endothelial cells

Stickstoffdioxid [MAK Value Documentation in German language, 2003]

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