Evidence of nuclear localization of neuronal nitric oxide synthase in cultured astrocytes of rats

Yuan, Zhonghua; Liu, Baoyi; Yuan, Lan; Zhang, Ye; Dong, Xiaomin; Lu, Jingfen

doi:10.1016/j.lfs.2003.10.037

Cited by 35 publications

(19 citation statements)

References 24 publications

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“…4A), similar to previously published data from several different groups (4,9,16). Interestingly, nNOS demonstrated a prominent nuclear localization, similar to the findings by several other groups (43,48), the significance of which in endothelial cells (such as on the regulation of protein expression) is currently being examined in our laboratory. We further confirmed the nuclear location of nNOS by confocal microscopy (Fig.…”

Section: E 2 Attenuates High Glucose-induced Nitrotyrosine and Peroxysupporting

confidence: 84%

Estradiol attenuates high glucose-induced endothelial nitrotyrosine: role for neuronal nitric oxide synthase

Chakrabarti

Cheung

Davidge

2012

American Journal of Physiology-Cell Physiology

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Chakrabarti S, Cheung CC, Davidge ST. Estradiol attenuates high glucose-induced endothelial nitrotyrosine: role for neuronal nitric oxide synthase. Am J Physiol Cell Physiol 302: C666 -C675, 2012. First published November 30, 2011 doi:10.1152/ajpcell.00181.2011.-Hyperglycemia in diabetes causes increased oxidative stress in the vascular endothelium with generation of free radicals such as superoxide. Peroxynitrite, a highly reactive species generated from superoxide and nitric oxide (NO), induces proinflammatory tyrosine nitration of intracellular proteins under such conditions. The female sex hormone estrogen appears to exert protective effects on the nondiabetic endothelium. However, several studies show reduced vascular protection in women with diabetes, suggesting alterations in estrogen signaling under high glucose. In this study, we examined the endothelial effects of estrogen under increasing glucose levels, focusing on nitrotyrosine and peroxynitrite. Human umbilical vein endothelial cells were incubated with normal (5.5 mM) or high (15.5 or 30.5 mM) glucose before addition of estradiol (E 2, 1 or 10 nM). Selective NO synthase (NOS) inhibitors were used to determine the role of specific NOS isoforms. Addition of E2 significantly reduced high glucoseinduced increase in peroxynitrite and consequently, nitrotyrosine. The superoxide levels were unchanged, suggesting effects on NO generation. Inhibition of neuronal NOS (nNOS) reduced high glucoseinduced nitrotyrosine, demonstrating a critical role for this enzyme. E2 increased nNOS activity under normal glucose while decreasing it under high glucose as determined by its phosphorylation status. These data show that nNOS contributes to endothelial peroxynitrite and subsequent nitrotyrosine generation under high glucose, which can be attenuated by E2 through nNOS inhibition. The altered regulation of nNOS by E2 under high glucose is a potential therapeutic target in women with diabetes.

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Section: E 2 Attenuates High Glucose-induced Nitrotyrosine and Peroxysupporting

confidence: 84%

Estradiol attenuates high glucose-induced endothelial nitrotyrosine: role for neuronal nitric oxide synthase

Chakrabarti

Cheung

Davidge

2012

American Journal of Physiology-Cell Physiology

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“…Thus expression changes of NOS1 can reflect the activation of functional NMDA-R [9,10,62]. NOS1 expression has been observed in cultured astrocytes [63], but ischemia-induced NOS1 up-regulation in astrocytes has not been reported. The dose-dependent inhibitory effect of MK-801 on ischemiainduced NOS1 up-regulation confirmed that astrocytes possess functional NMDA-R and demonstrated that the increase of NOS1 protein in astrocytes under ischemia was attributable to activation of NMDA-R in astrocytes.…”

Section: Discussionmentioning

confidence: 98%

Astrocytes Express N-Methyl-D-Aspartate Receptor Subunits in Development, Ischemia and Post-Ischemia

Zhou

Zhao

et al. 2010

Neurochem Res

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The expression of the N-methyl-D-aspartate receptor (NMDA-R) in astrocytes is controversial. The receptor is commonly considered neuron-specific. We showed that astrocytes in primary cultures differentially expressed mRNA of NMDA-R subunits, NR1, NR2A and NR2B, in development, ischemia and post-ischemia. One-week-old cultures expressed detectable NR1 mRNA, which fell significantly at 2 weeks and became barely detectable at 4 weeks. NR2A and NR2B mRNA were both significantly up-regulated from 1 to 2 weeks. In 4 weeks, 2 h of ischemia caused a significant up-regulation of NR1 and NR2B mRNA; while 6 h caused down-regulation of NR2A mRNA. Under 3 h of post-ischemia, only NR1 mRNA was increased. Ischemia induced the expression of major NMDA-R effecter, nitric oxide synthase 1, which was unaffected by AMPA-R antagonist CNQX, but dose-dependently inhibited by NMDA-R specific antagonist MK-801. These findings reflected that astrocyte could express inducible functional NMDA receptors without the presence of neurons.

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“…The possibility of contaminating cells is unlikely since neither astrocytes or microglia are known to induce or activate nNOS (Brannan and Roberts, 2004). Constitutive expression of nNOS in astrocytes has been reported but activation and induction of nNOS by LPS has not been described (Tolias et al, 1999; Yuan et al, 2004a). There have been no reports of nNOS induction in microglial cells treated with LPS, hence, the activation of nNOS appear to be predominantly in oligodendrocytes.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo induction and activation of nNOS by LPS in oligodendrocytes

Yao¹,

Ljunggren-Rose²,

Chandramohan³

et al. 2010

Journal of Neuroimmunology

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There are currently four known isoforms of nitric oxide synthase (NOS). Of these, neuronal NOS (nNOS) is known to be present exclusively in neurons, endothelial NOS (eNOS) in vascular endothelium, while the inducible form of NOS (iNOS) is known to be activated in oligodendrocytes, astrocytes and microglia. The fourth isoform, mitochondrial NOS (mtNOS), represents a post translational modification of nNOS. Using western blotting and real time-PCR, we show induction and activation of nNOS following culture of oligodendrocyte progenitor cells (OPC) with lipopolysaccharide (LPS). Activation of nNOS results in accumulation of peroxynitrite and tyrosine nitration of proteins in oligodendrocytes resulting in reduced cell viability. Injection of LPS in vivo into the corpus callosum of rats leads to the development of extensive demyelination of the white matter tracts. Immunostaining of regions close to the injection site shows the presence of nNOS, but not iNOS, in oligodendrocytes. Neither iNOS nor nNOS was seen in astrocytes in areas of demyelination. These studies suggest that activation of nNOS in oligodendrocytes leads to oligodendrocyte injury resulting in demyelination.

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Evidence of nuclear localization of neuronal nitric oxide synthase in cultured astrocytes of rats

Cited by 35 publications

References 24 publications

Estradiol attenuates high glucose-induced endothelial nitrotyrosine: role for neuronal nitric oxide synthase

Estradiol attenuates high glucose-induced endothelial nitrotyrosine: role for neuronal nitric oxide synthase

Astrocytes Express N-Methyl-D-Aspartate Receptor Subunits in Development, Ischemia and Post-Ischemia

In vitro and in vivo induction and activation of nNOS by LPS in oligodendrocytes

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