Strong nuclear factor-?B-DNA binding parallels cyclooxygenase-2 gene transcription in aging and in sporadic alzheimer's disease superior temporal lobe neocortex

Lukiw, Walter J.; Bazán, Nicolás G.

doi:10.1002/(sici)1097-4547(19980901)53:5<583::aid-jnr8>3.0.co;2-5

Cited by 168 publications

(31 citation statements)

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“…It was shown previously that inducible PGHS-2 is upregulated with aging and oxidative stress (18,21,30). Moreover, our lab reported (30) that PGHS-2-dependent vasoconstriction is increased with age, which was associated with increased PGHS-2 expression.…”

Section: Discussionsupporting

confidence: 52%

“…Peroxynitrite reduces the expression and activity of prostacyclin synthase (6,38), the enzyme that produces the vasorelaxant prostacyclin. Also, reactive oxygen species such as superoxide have been shown to enhance the formation of inducible PGHS-2 through activation of the nuclear transcription factor nuclear factor (NF)-B in the rat kidney (18) and in aging brain cells (21). More recently, we showed (30) that PGHS-2 protein expression is upregulated with aging in rat mesenteric arteries and that vessel tone is increased via this eicosanoid pathway.…”

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confidence: 96%

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Estrogen replacement reduces PGHS-2-dependent vasoconstriction in the aged rat

Armstrong

Zhang

Stewart

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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art, and Sandra T. Davidge. Estrogen replacement reduces PGHS-2-dependent vasoconstriction in the aged rat. Am J Physiol Heart Circ Physiol 283: H893-H898, 2002. First published May 16, 2002 10.1152/ajpheart.00148. 2002. The reduction in estrogen in postmenopausal women contributes to an increase in vascular dysfunction. Models of aging have shown that this is due, in part, to increased prostaglandin H synthase (PGHS)-dependent vasoconstriction. We showed previously that inducible PGHS-2-dependent vasoconstriction is increased with aging. In the present study, we hypothesized that estrogen suppresses PGHS-2-dependent constriction in the aged rat. Isolated mesenteric arteries from placebo-or estrogen-treated, ovariectomized aged (24 mo) Fisher rats were assessed for endotheliumdependent relaxation in the absence or presence of PGHS inhibitors. PGHS inhibition (meclofenamate, 1 mol/l) enhanced methacholine-induced relaxation only in the placebo group. Specific PGHS-2 inhibition (NS-398, 10 mol/l) increased arterial relaxation to a greater extent than PGHS-1 inhibition (valeryl salicylate, 3 mmol/l). Estrogen prevented the PGHS-dependent constrictor effect but did not enhance nitric oxide-dependent relaxation in this model. PGHS-1 and endothelial nitric oxide synthase were not altered by estrogen, whereas PGHS-2 expression was decreased in the estrogen-replaced rats (P Ͻ 0.05). In summary, estrogen replacement improved vasodilation in aged rats by decreasing PGHS-dependent constriction. mesenteric arteries; prostaglandin H synthase; nitric oxide; NS-398 AFTER MENOPAUSE, women become more susceptible to cardiovascular dysfunction, largely as a result of the estrogen deficit that is incurred (22,28). This lack of estrogen has been found to affect vascular function, not only by loss of protection of favorable blood lipid levels (19) but also through direct mechanisms. Numerous studies have focused on the effect of estrogen on endothelial modulation of vascular tone by nitric oxide (NO). For instance, estrogen replacement is thought to improve relaxation by elevating the expression of endothelial NO synthase (eNOS) and subsequently producing more NO (13,25,36). In addition, estrogen enhances the bioavailability of NO by inhibiting superoxide anion production (2). However, not all of the vascular effects of estrogen can be attributed to the NO pathway.Our laboratory (9, 29) has demonstrated the importance of estrogen in the prostaglandin H synthase (PGHS) pathway. Our data (9) indicated that estrogen suppresses PGHS-dependent vasoconstriction in an ovariectomized rat model. However, this study as well as previous studies regarding estrogen replacement in ovariectomized animals has largely been conducted with young adult animal models (5,14,16,33). Importantly, the physiological processes due to aging (which are important relative to effects on postmenopausal women) are not taken into account with this model. For instance, the aging process contributes to enhanced oxidative stress on the vasculature, which could lead t...

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Section: Discussionsupporting

confidence: 52%

mentioning

confidence: 96%

Estrogen replacement reduces PGHS-2-dependent vasoconstriction in the aged rat

Armstrong

Zhang

Stewart

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…For instance, Kaltschmidt et al (28) show that exposure of neurons to the phorbol 12-myristate 13-acetate (PMA) increases neuronal COX-2 expression in an NF-B -dependent manner. Additionally, NFB is regarded as a strong regulator of inducible COX-2 expression in neurons from diseased brain (29,30) and spinal cord (31,32). Thus, synaptic activity-dependent constitutive COX-2 expression is mechanistically different from injury-induced COX-2 expression.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous Glutamatergic Synaptic Activity Regulates Constitutive COX-2 Expression in Neurons OPPOSING ROLES FOR THE TRANSCRIPTION FACTORS CREB (cAMP RESPONSE ELEMENT BINDING) PROTEIN AND Sp1 (STIMULATORY PROTEIN-1)

Hewett

Shi

Gong

et al. 2016

Journal of Biological Chemistry

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Edited by Paul E. FraserBurgeoning evidence supports a role for cyclooxygenase metabolites in regulating membrane excitability in various forms of synaptic plasticity. Two cyclooxygenases, COX-1 and COX-2, catalyze the initial step in the metabolism of arachidonic acid to prostaglandins. COX-2 is generally considered inducible, but in glutamatergic neurons in some brain regions, including the cerebral cortex, it is constitutively expressed. However, the transcriptional mechanisms by which this occurs have not been elucidated. Here, we used quantitative PCR and also analyzed reporter gene expression in a mouse line carrying a construct consisting of a portion of the proximal promoter region of the mouse COX-2 gene upstream of luciferase cDNA to characterize COX-2 basal transcriptional regulation in cortical neurons. Extracts from the whole brain and from the cerebral cortex, hippocampus, and olfactory bulbs exhibited high luciferase activity. Moreover, constitutive COX-2 expression and luciferase activity were detected in cortical neurons, but not in cortical astrocytes, cultured from wild-type and transgenic mice, respectively. Constitutive COX-2 expression depended on spontaneous but not evoked excitatory synaptic activity and was shown to be N-methyl-D-aspartate receptor-dependent. Constitutive promoter activity was reduced in neurons transfected with a dominant-negative cAMP response element binding protein (CREB) and was eliminated by mutating the CRE-binding site on the COX-2 promoter. However, mutation of the stimulatory protein-1 (Sp1)-binding site resulted in an N-methyl-D-aspartate receptor-dependent enhancement of COX-2 promoter activity. Basal binding of the transcription factors CREB and Sp1 to the native neuronal COX-2 promoter was confirmed. In toto, our data suggest that spontaneous glutamatergic synaptic activity regulates constitutive neuronal COX-2 expression via Sp1 and CREB protein-dependent transcriptional mechanisms.The first committed reaction in the metabolism of arachidonic acid to prostaglandins and thromboxanes is catalyzed by two related heme-containing bis-oxygenases, cyclooxygenase (COX) 1 and 2. These enzymes share 90% similarity in amino acid sequence and exhibit nearly identical enzyme kinetics (1, 2). Both catalyze two separate reactions, the first metabolizing arachidonic acid to PGG 2 3 (cyclooxygenase reaction), an intermediate that is subsequently reduced in the second reaction to the product, PGH 2 (peroxidase reaction). PGH 2 is the substrate for various synthases that generate individual biologically active prostaglandins and thromboxanes, often in a cell typespecific manner (3). Although both metabolize arachidonic acid to PGH 2 , the transcriptional regulation of each isoform differs. The PTGS1 gene encoding COX-1 lacks a TATA box motif in its 5Ј promoter region and is generally constitutively active in cells (4, 5). In contrast, the promoter regulatory region of the PTGS2 gene encoding COX-2 is not typically active but can be strongly and rapidly induced under specific...

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“…significantly correlated to an elevation in a key inflammatory enzyme COX-2, in both aging and AD temporal lobe neocortex [65].…”

Section: Role Of Reactive Oxygen Species In Biological Systemsmentioning

confidence: 95%

Mechanisms by which metals promote events connected to neurodegenerative diseases

Campbell

Smith

Sayre

et al. 2001

Brain Research Bulletin

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Although the exact causative phenomenon responsible for the onset and progression of neurodegenerative disorders is at present unresolved, there are some clues as to the mechanisms underlying these chronic diseases. This review addresses mechanisms by which endogenous or environmental factors, through interaction with redox active metals, may initiate a common cascade of events terminating in neurodegeneration.

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Strong nuclear factor-?B-DNA binding parallels cyclooxygenase-2 gene transcription in aging and in sporadic alzheimer's disease superior temporal lobe neocortex

Cited by 168 publications

References 63 publications

Estrogen replacement reduces PGHS-2-dependent vasoconstriction in the aged rat

Estrogen replacement reduces PGHS-2-dependent vasoconstriction in the aged rat

Spontaneous Glutamatergic Synaptic Activity Regulates Constitutive COX-2 Expression in Neurons OPPOSING ROLES FOR THE TRANSCRIPTION FACTORS CREB (cAMP RESPONSE ELEMENT BINDING) PROTEIN AND Sp1 (STIMULATORY PROTEIN-1)

Mechanisms by which metals promote events connected to neurodegenerative diseases

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