Cyclooxygenase-2-dependent neuronal death proceeds via superoxide anion generation

Im, Joo Young; Kim, Do-Yeun; Paik, Sang Gi; Han, Pyung Lim

doi:10.1016/j.freeradbiomed.2006.06.001

Cited by 91 publications

(75 citation statements)

References 59 publications

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“…2B), suggesting that the increased cutaneous blood flow induced by COX inhibition is a result of a KCa channel-dependent mechanism(s). COX can increase superoxide (22), which may result in an attenuated KCa channel activity secondary to increased peroxynitrite formation, as discussed above. Alternatively, aging may lead to increases in COX-derived thromboxane A2 (46), which can also inhibit KCa channel activity (50).…”

Section: Discussionmentioning

confidence: 97%

Cutaneous blood flow during intradermal NO administration in young and older adults: roles for calcium-activated potassium channels and cyclooxygenase?

Fujii

Meade

Brunt

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Fujii N, Meade RD, Minson CT, Brunt VE, Boulay P, Sigal RJ, Kenny GP. Cutaneous blood flow during intradermal NO administration in young and older adults: roles for calcium-activated potassium channels and cyclooxygenase?. Am J Physiol Regul Integr Comp Physiol 310: R1081-R1087, 2016. First published April 13 2016; doi:10.1152/ajpregu.00041.2016.-Nitric oxide (NO) increases cutaneous blood flow; however, the underpinning mechanism(s) remains to be elucidated. We hypothesized that the cutaneous blood flow response during intradermal administration of sodium nitroprusside (SNP, a NO donor) is regulated by calcium-activated potassium (KCa) channels and cyclooxygenase (COX) in young adults. We also hypothesized that these contributions are diminished in older adults given that aging can downregulate KCa channels and reduce COXderived vasodilator prostanoids. In 10 young (23 Ϯ 5 yr) and 10 older (54 Ϯ 4 yr) adults, cutaneous vascular conductance (CVC) was measured at four forearm skin sites infused with 1) Ringer (Control), 2) 50 mM tetraethylammonium (TEA), a nonspecific KCa channel blocker, 3) 10 mM ketorolac, a nonspecific COX inhibitor, or 4) 50 mM TEA ϩ 10 mM ketorolac via intradermal microdialysis. All skin sites were coinfused with incremental doses of SNP (0.005, 0.05, 0.5, 5, and 50 mM each for 25 min). During SNP administration, CVC was similar at the ketorolac site (0.005-50 mM, all P Ͼ 0.05) relative to Control, but lower at the TEA and TEA ϩ ketorolac sites (0.005-0.05 mM, all P Ͻ 0.05) in young adults. In older adults, ketorolac increased CVC relative to Control during 0.005-0.05 mM SNP administration (all P Ͻ 0.05), but this increase was not observed when TEA was coadministered (all P Ͼ 0.05). Furthermore, TEA alone did not modulate CVC during any concentration of SNP administration in older adults (all P Ͼ 0.05). We show that during low-dose NO administration (e.g., 0.005-0.05 mM), KCa channels contribute to cutaneous blood flow regulation in young adults; however, in older adults, COX inhibition increases cutaneous blood flow through a KCa channel-dependent mechanism.aging; smooth muscle cell; endothelial cell; microcirculation; endothelium-derived hyperpolarizing factors; prostanoids; soluble guanylyl cyclase; nitric oxide synthase NITRIC OXIDE (NO) produced from NO synthase (NOS) contributes to the regulation of cutaneous blood flow during local or whole body heating (15,17,23,24,37,38,40,(51)(52)(53). NO appears to cause vasodilation by directly influencing vascular smooth muscle cells through soluble guanylyl cyclase-dependent signaling cascades (25). Thus exogenous administration of NO donor such as sodium nitroprusside (SNP), for instance, is widely used to assess endothelium-independent vasodilation (i.e., vascular smooth muscle cell function). However, exogenous NO-induced vasodilation may not necessarily reflect endothelium-independent vasodilation since NO can influence other pathways. In line with this, local heating-induced transient cutaneous vasodilation, which is mainly mediated by sen...

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Section: Discussionmentioning

confidence: 97%

Cutaneous blood flow during intradermal NO administration in young and older adults: roles for calcium-activated potassium channels and cyclooxygenase?

Fujii

Meade

Brunt

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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“…COX-2 has an epidermal growth factor (EGF)-like domain at its NH 2 terminus that functions in Ca 2+ -related signaling pathways such as the protein kinase C (PKC) pathway, whereas the COOH terminus has a peroxidase domain that acts in cellular oxidation and reduction. Thus, COX-2 is a bifunctional enzyme that has both cyclooxygenase and peroxidase activities (10,11). Cyclooxygenase activity of COX-2 transforms arachidonic acid into intermediate prostaglandin G 2 , which is subsequently converted to prostaglandin H 2 through peroxidase activity, and finally, prostaglandins [prostaglandin E 2 (PGE 2 ), prostaglandin D 2 , prostaglandin F 2 α, thromboxane A, etc.]…”

Section: Introductionmentioning

confidence: 99%

“…Cyclooxygenase activity of COX-2 transforms arachidonic acid into intermediate prostaglandin G 2 , which is subsequently converted to prostaglandin H 2 through peroxidase activity, and finally, prostaglandins [prostaglandin E 2 (PGE 2 ), prostaglandin D 2 , prostaglandin F 2 α, thromboxane A, etc.] are produced by various synthases (6,11,12).…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase-2 (COX-2) Negatively Regulates Expression of Epidermal Growth Factor Receptor and Causes Resistance to Gefitinib in COX-2–Overexpressing Cancer Cells

Kim

Park

Pyo

2009

Molecular Cancer Research

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Overexpression of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) has been detected in many types of cancer. Although COX-2 and EGFR are closely related to each other, the exact mechanism of COX-2 in tumors has not been well understood. In this study, we investigated the relationship between COX-2 and EGFR in cancer cells. Using two cell lines stably overexpressing COX-2 (HCT-116-COX-2 and H460-COX-2) and a stable line of COX-2 knockdown MOR-P cells, we analyzed patterns of COX-2 and EGFR expression. To observe the effects of COX-2 on EGFR expression and activity, we did comparative analyses after treatment with various drugs (EGF, celecoxib, prostaglandin E 2 , gefitinib, Ro-31-8425, PD98059, and SP600125) in HCT-116-Mock versus HCT-116-COX-2 cells and H460-Mock versus H460-COX-2 cells. Overexpression of COX-2 specifically down-regulated EGFR expression at the level of transcription. COX-2-overexpressing cells have a decreased sensitivity to gefitinib. COX-2 induced activation of extracellular signal-regulated kinase (ERK) and c-Jun NH 2 -terminal kinase (JNK) but suppressed Akt activation. JNK inhibition by SP600125, a specific JNK inhibitor, resulted in restoration of EGFR levels in COX-2-overexpressing cells, whereas ERK inhibition by PD98059 did not. Overexpressed COX-2 negatively regulates EGFR expression via JNK activation, leading to gefitinib resistance. COX-2 may also regulate ERK activity independently of EGFR. Therefore, resistance of COX-2-overexpressing cells to gefitinib may be due to decreased expression of EGFR by JNK activation and EGFR-independent elevation of ERK activity by COX-2. The ability of COX-2 to inhibit EGFR expression and gefitinib effects may have significance in clinical cancer therapy.

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“…However, the most relevant interaction of these two systems may be related to the generation of superoxide (O 2 Ϫ ) by COX-2. O 2 Ϫ is generated by constitutive COX-2 in neural cells (15), in the gastric mucosa (33), in cerebral arteries under normal conditions (4), in the aorta in endotoxic shock (34), and in the diabetic kidney (20 Ϫ generated by MD COX-2 reacts with NO to reduce NO. During COX-2 inhibition, there is more NO available, which enhances the Pxb effect on TGF.…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase 2 inhibition suppresses tubuloglomerular feedback: roles of thromboxane receptors and nitric oxide

Araújo

Welch²

2009

American Journal of Physiology-Renal Physiology

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Araujo M, Welch WJ. Cyclooxygenase 2 inhibition suppresses tubuloglomerular feedback: roles of thromboxane receptors and nitric oxide. Am J Physiol Renal Physiol 296: F790 -F794, 2009. First published January 14, 2009 doi:10.1152/ajprenal.90446.2008 and nitric oxide (NO) are potent vasoactive autocoids that modulate tubuloglomerular feedback (TGF). Each is produced in the macula densa (MD) by cyclooxygenase-2 (COX-2) and neuronal nitric oxide synthase (nNOS), respectively. Both enzymes are similarly regulated in the MD and their interaction may be an important factor in the regulation of TGF and glomerular filtration rate. We tested the hypothesis that TGF is modified by the balance between MD nNOS-dependent NO and MD COX-2-dependent TxA2. We measured maximal TGF during perfusion of the loop of Henle (LH) by continuous recording of the proximal tubule stopped flow pressure response to LH perfusion of artificial tubular fluid (ATF) at 0 and 40 nl/min. The response to inhibitors of COX-1 (SC-560), COX-2 [parecoxib (Pxb)], and nNOS (L-NPA) added to the ATF solution was measured in separate nephrons. COX-2 inhibition with Pxb reduced TGF by 46% (ATF ϩ vehicle vs. ATF ϩ Pxb), whereas COX-1 inhibition with SC-560 reduced TGF by only 23%. Pretreatment with intravenous infusion of SQ-29,548, a selective thromboxone/PGH2 receptor (TPR) antagonist, blocked all of the SC-560 effect on TGF, suggesting that this effect was due to activation of TPR. However, SQ-29,548 only partially diminished the effect of Pxb (Ϫ66%). Specific inhibition of nNOS with L-NPA increased TGF, as expected. However, the ability of Pxb to reduce TGF was significantly impaired with comicroperfusion of L-NPA. These data suggest that COX-2 modulates TGF by two proconstrictive actions: generation of TxA2 acting on TPR and by simultaneous reduction of NO. blood flow; systemic volume; electrolyte homeostasis THE KIDNEY'S ABILITY to regulate its blood flow is a major factor in maintaining systemic volume and electrolyte homeostasis. Renal autoregulation is regulated by two distinct, but possibly interactive, systems that maintain stable renal blood flow (RBF): the vascular myogenic reflex and tubuloglomerular feedback (TGF). Renal myogenic control reflects changes in pressure that generate compensatory changes in tone to maintain consistent flow and is similar to extrarenal vascular regulation. TGF, however, is unique to the kidney and maintains vascular tone in response to the changes in solute delivery sensed at the macula densa (MD) segment of each nephron. TGF acts to stabilize glomerular filtration rate (GFR) by regulating RBF during acute challenges, such as volume, flow, or pressure changes. TGF is mediated by locally generated adenosine acting on receptors in the vessels that alters microvascular tone. However, multiple autocoids and hormones modify TGF; including ATP, ANG II, nitric oxide (NO), prostaglandins (PG), and thromboxane (TxA 2 ) all of which are generated in the juxtaglomerular apparatus.PGs and TxA 2 are produced by specific enzymes a...

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Cyclooxygenase-2-dependent neuronal death proceeds via superoxide anion generation

Cited by 91 publications

References 59 publications

Cutaneous blood flow during intradermal NO administration in young and older adults: roles for calcium-activated potassium channels and cyclooxygenase?

Cutaneous blood flow during intradermal NO administration in young and older adults: roles for calcium-activated potassium channels and cyclooxygenase?

Cyclooxygenase-2 (COX-2) Negatively Regulates Expression of Epidermal Growth Factor Receptor and Causes Resistance to Gefitinib in COX-2–Overexpressing Cancer Cells

Cyclooxygenase 2 inhibition suppresses tubuloglomerular feedback: roles of thromboxane receptors and nitric oxide

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