Regulation of xanthine dehydrogenase and xanthine oxidase activity by hypoxia

Poss, W. Bradley; Huecksteadt, Thomas P.; Panus, Peter C.; Freeman, Bruce Α.; Hoidal, John R.

doi:10.1152/ajplung.1996.270.6.l941

Cited by 50 publications

(51 citation statements)

References 27 publications

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“…We found that hypoxia-mediated XDH/XO activation is dependent on the JAK/ STAT pathway in primary cultures of LMVEC. We demonstrated that the XDH/XO activity significantly increased by hypoxia, consistent with the increased phosphorylation or activation of XDH/XO in response to hypoxia in other cells (Terada et al, 1992;Dupont et al, 1992;Kayyali et al, 2001;Mervaala et al, 2001;Terada et al, 1997;Poss et al, 1996;Sohn et al, 2003;Kang et al, 2006). Interestingly, our data demonstrated that XDH/XO activation induced by could be inhibited by either depletion of IL6 using IL6 antibodies, pretreatment with the JAK2 inhibitor AG490 or transient expression of the JAK-STAT pathway blocker SOCS3 and their inhibitory effect on the XDH/XO activation was at a similar magnitude.…”

Section: Discussionsupporting

confidence: 82%

“…It has been demonstrated that hypoxia activates XDH/XO, an important source of reactive oxygen species (ROS) (Terada et al, 1992;Dupont et al, 1992;Kayyali et al, 2001;Mervaala et al, 2001;Terada et al, 1997;Poss et al, 1996;Sohn et al, 2003;Kang et al, 2006). However, the molecular mechanism underlying the hypoxia-mediated activation of XDH/XO remains largely unknown.…”

Section: Discussionmentioning

confidence: 99%

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Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells

Wang

Pei

Jackson

et al. 2008

The International Journal of Biochemistry & Cell Biology

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Xanthine dehydrogenase/oxidase (XDH/XO) is associated with various pathological conditions related to the endothelial injury. However, the molecular mechanism underlying the activation of XDH/XO by hypoxia remains largely unknown. In this report, we determined whether the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) signaling pathway is involved in hypoxia-induced activation of XDH/XO in primary cultures of lung microvascular endothelial cells (LMVEC). We found that hypoxia significantly increased interleukin 6 (IL6) production in a time-dependent manner in LMVEC. Hypoxia also markedly augmented phosphorylation/activation of JAKs (JAK1, JAK2 and JAK3) and the JAK downstream effectors STATs (STAT3 and STAT5). Hypoxia-induced activation of STAT3 was blocked by IL6 antibodies, the JAK inhibitor AG490 and the suppressor of cytokine signaling 3 (SOCS3), implying that hypoxiapromoted IL6 secretion activates the JAK/STAT pathway in LMVEC. Phosphorylation and DNAbinding activity of STAT3 was also inhibited by the p38 MAPK inhibitor SB203580 and the phosphatidylinositol 3-kinase inhibitor LY294002, suggesting that multiple signaling pathways involved in STAT activation by hypoxia. Importantly, hypoxia promoted XDH/XO activation in LMVEC, which was markedly reversed by inhibiting the JAK/STAT pathway using IL6 antibodies, AG490 and SOCS3. These data demonstrated that JAKs, STATs and XDH/XO were sequentially activated by hypoxia. These data also provide the first evidence indicating that the JAK-STAT pathway is involved in hypoxia-mediated XDH/XO activation in LMVEC.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells

Wang

Pei

Jackson

et al. 2008

The International Journal of Biochemistry & Cell Biology

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“…Under normal conditions, the enzyme xanthine oxidoreductase (XOR) exists primarily in its dehydrogenase form, serving as the rate-limiting step in purine degradation to uric acid. Under conditions of tissue hypoxia (53), ATP is broken down to the purine hypoxanthine, a substrate for XOR, and reversible oxidation or irreversible proteolytic cleavage (17,54), which converts XOR to an oxidase form that can produce large quantities of ROS, including O 2 •Ϫ and its dismutation product, hydrogen peroxide (H 2 O 2 ). In adults, increased vascular O 2 •Ϫ production during chronic exposure to hypoxia has been attributed in major part to XO, which has been found to adversely impact endothelial function by impairing nitric oxide (NO) signaling (26) and to directly contribute to experimental pulmonary vascular remodeling (25).…”

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confidence: 99%

Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats

Jankov¹,

Kantores²,

Pan³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

117

105

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Jankov RP, Kantores C, Pan J, Belik J. Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats. Am J Physiol Lung Cell Mol Physiol 294: L233-L245, 2008. First published December 14, 2007 doi:10.1152/ajplung.00166.2007.-Xanthine oxidase (XO)-derived reactive oxygen species (ROS) formation contributes to experimental chronic hypoxic pulmonary hypertension in adults, but its role in neonatal pulmonary hypertension has received little attention. In rats chronically exposed to hypoxia (13% O2) for 14 days from birth, we examined the effects of ROS scavengers (U74389G 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 or Tempol 100 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ip) or a XO inhibitor, Allopurinol (50 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ip). Both ROS scavengers limited oxidative stress in the lung and attenuated hypoxia-induced vascular remodeling, confirming a critical role for ROS in this model. However, both interventions also significantly inhibited somatic growth and normal cellular proliferation in distal air spaces. Hypoxiaexposed pups had evidence of increased serum and lung XO activity, increased vascular XO-derived superoxide production, and vascular nitrotyrosine formation. These changes were all prevented by treatment with Allopurinol, which also attenuated hypoxia-induced vascular remodeling and partially reversed inhibited endothelium-dependent arterial relaxation, without affecting normal growth and proliferation. Collectively, our findings suggest that XO-derived superoxide induces endothelial dysfunction, thus impairing pulmonary arterial relaxation, and contributes to vascular remodeling in hypoxia-exposed neonatal rats. Due to the potential for adverse effects on normal growth, targeting XO may represent a superior "antioxidant" strategy to ROS scavengers for neonates with pulmonary hypertension.antioxidants; allopurinol; U74389G; Tempol; 8-isoprostane PULMONARY HYPERTENSION (PHT) is a common condition of the critically ill neonate (12,18,52,64,65). An increased propensity to PHT in the newborn period, compared with other stages of life, is predominantly related to two factors: a failure in the physiological fall in pulmonary vascular resistance required for a successful transition to postnatal life, and the rapid development of anatomical changes in the heart and pulmonary vasculature (23), known collectively as vascular remodeling. Evidence suggests that abnormally decreased pulmonary arterial relaxation is an early functional feature of PHT that directly contributes to the subsequent anatomical changes of remodeling (1). Together, these changes lead to narrowing of the vessel lumen, exaggerated responses to constrictors (3,14), and reduced compliance, all of which are believed to contribute to a chronic and progressive form of PHT that is refractory to current therapies (13).A major pathological role for increased generation of reactive oxygen species (ROS) in the pathogenesis of experimental PHT is evidenced by antioxidant intervention studies performed in fetal lambs (24, 39), in hyperoxia-exp...

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“…Hypoxia has been reported to increase XOR activity in cultured rat and bovine endothelial cells (11,28,38,39). The mechanism of the increase, however, is uncertain, because some studies have reported increases in XOR mRNA transcript levels (11,39), whereas another study failed to show any alterations in XOR gene expression by hypoxia (28).…”

mentioning

confidence: 99%

“…The mechanism of the increase, however, is uncertain, because some studies have reported increases in XOR mRNA transcript levels (11,39), whereas another study failed to show any alterations in XOR gene expression by hypoxia (28). Furthermore, phosphorylation of XOR in hypoxia has been suggested to account for increased XOR activity (21).…”

mentioning

confidence: 99%

Posttranslational inactivation of human xanthine oxidoreductase by oxygen under standard cell culture conditions

Linder

Martelin

Lapatto

et al. 2003

American Journal of Physiology-Cell Physiology

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O. Raivio. Posttranslational inactivation of human xanthine oxidoreductase by oxygen under standard cell culture conditions. Am J Physiol Cell Physiol 285: C48-C55, 2003. First published March 12, 2003 10.1152/ajpcell.00561.2002 catalyzes the final reactions of purine catabolism and may account for cell damage by producing reactive oxygen metabolites in cells reoxygenated after hypoxia. We found a three-to eightfold higher XOR activity in cultured human bronchial epithelial cells exposed to hypoxia (0.5-3% O 2) compared with cells grown in normoxia (21% O 2) but no difference in XOR protein or mRNA. XOR promoter constructs failed to respond to hypoxia. The cellular XOR activity at 3% O 2 returned to basal levels when the cells were returned to 21% O 2, and hyperoxia (95% O2) abolished enzyme activity with no change in XOR protein.Our data suggest reversible enzyme inactivation by oxygen or its metabolites. NADH was normally oxidized by the oxygen-inactivated enzyme, which rules out damage to the flavin adenine dinucleotide cofactor. Hydrogen peroxide partially inactivated the molybdenum center of XOR, as shown by a parallel decrease in XOR-catalyzed xanthine oxidation and dichlorophenolindophenol reduction. We conclude that the transcription or translation of XOR is not influenced by hypoxia or hyperoxia. Instead, the molybdenum center of XOR is posttranslationally inactivated by oxygen metabolites in "normal" (21% O 2) cell culture atmosphere. This inactivation is reversed in hypoxia and accounts for the apparent induction. xanthine oxidase; hypoxia; hyperoxia; ischemia reperfusion

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Regulation of xanthine dehydrogenase and xanthine oxidase activity by hypoxia

Cited by 50 publications

References 27 publications

Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells

Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells

Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats

Posttranslational inactivation of human xanthine oxidoreductase by oxygen under standard cell culture conditions

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