Allopurinol modulates reactive oxygen species generation and Ca2+ overload in ischemia-reperfused heart and hypoxia-reoxygenated cardiomyocytes

Kang, Seok‐Min; Lim, Soyeon; Song, Heesang; Chang, Won Hyuk; Lee, Sun-Ju; Bae, Sangmee; Chung, Ji Hyung; Lee, Hakbae; Kim, Ho-Gyoung; Yoon, Deok-Hyo; Kim, Tae‐Woong; Jang, Yangsoo; Sung, Jae-Mo; Chung, Namsik; Hwang, Ki‐Chul

doi:10.1016/j.ejphar.2006.01.013

Cited by 69 publications

(44 citation statements)

References 28 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: 81%

“…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: 81%

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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“…Its adaptive metabolite, oxypurinol, can provide some protection against I/R injury by suppressing the production of ROS and Ca 2+ overload 11 . Allopurinol has been reported to attenuate reperfusion injury in various organs 12 . Moreover, tubular cell apoptosis has been found to be a major factor involved in the mechanism of renal IR injury 13 .…”

Section: Introductionmentioning

confidence: 99%

Allopurinol preconditioning attenuates renal ischemia/reperfusion injury by inhibiting HMGB1 expression in a rat model

et al. 2016

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PURPOSE:To investigate the potential effects of pretreatment with allopurinol on renal ischemia/reperfusion injury (IRI) in a rat model. METHODS:Twenty four rats were subjected to right kidney uninephrectomy were randomly distributed into the following three groups (n=8): Group A (sham-operated group); Group B (ischemic group) with 30 min of renal ischemia after surgery; and Group C (allopurinol + ischemia group) pretreated with allopurinol at 50 mg/kg for 14 days. At 72 h after renal reperfusion, the kidney was harvested to assess inflammation and apoptosis. RESULTS:Pretreatment with allopurinol significantly improved renal functional and histological grade scores following I/R injury (p<0.05). Compared with Group B, the expression levels of caspase-3 and Bax were markedly reduced in Group C, meanwhile, whereas expression of bcl-2 was clearly increased (p<0.05). A newly described marker of inflammation, High Mobility Group Box 1(HMGB1), showed reduced expression in Group C (p<0.05). CONCLUSION:Pretreatment with allopurinol had a protective effect on kidney ischemia/reperfusion injury, which might be related to the inhibition of HMGB1 expression.Key words: Inflammation. Ischemia. Reperfusion. Allopurinol. Apoptosis. Rats. Allopurinol preconditioning attenuates renal ischemia/reperfusion injury by inhibiting HMGB1 expression in a rat model

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“…Cytosolic calcium accumulation has been proposed as a mediator of the pathogenic changes that occur during myocardial I/R [1,2] . Therefore, we tested the ability of astragaloside IV to prevent cytosolic Ca 2+ overload after reperfusion.…”

Section: Discussionmentioning

confidence: 99%

“…An excessive increase in the intracellular concentration of Ca 2+ would result in Ca 2+ overload and thus produce myocardial cell injury as presented in cardiomyopathic or ischemic-reperfused hearts [1,2] . Sarcoplasmic reticulum Ca 2+ -ATPase (SERCA2a), Na + -Ca 2+ exchanger, ryanodine receptor and L-type Ca 2+ channel are the major Ca 2+ -regulatory proteins responsible for intracellular Ca 2+ homeostasis throughout excitation-con-traction cycling in cardiomyocytes.…”

Section: Introductionmentioning

confidence: 99%

Astragaloside IV Improved Intracellular Calcium Handling in Hypoxia-Reoxygenated Cardiomyocytes via the Sarcoplasmic Reticulum Ca<sup>2+</sup>-ATPase

Chen

et al. 2008

Pharmacology

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Although astragaloside IV, a saponin isolated from Astragalus membranaceus, has been shown to protect the myocardium against ischemia/reperfusion injury, its effect on the status of sarcoplasmic reticulum (SR) Ca²⁺ transport in the injured myocardium remains largely unknown. In this study, we investigated whether in cultured cardiomyocytes subjected to hypoxia and reoxygenation (H/R) administration of astragaloside IV during H/R attenuates the myocardial cell injury and prevents changes in Ca²⁺ handling activities and gene expression of SR Ca²⁺ pump. Cultured cardiomyocytes from neonatal rats were exposed to 6 h of hypoxia followed by 3 h of reoxygenation. Myocyte injury was determined by the release of cardiac troponin I in supernatant. Astragaloside IV significantly inhibited cardiac troponin I release after H/R in a dose-dependent manner. The diastolic [Ca²⁺]_i measured with Fura-2/AM was significantly increased after reoxygenation. Astragaloside IV prevented the rise of diastolic [Ca²⁺]_i and the depression of caffeine-induced Ca²⁺ transients caused by H/R. Furthermore, the observed depressions in SR Ca²⁺-ATPase activity as well as the mRNA and protein expression of SR Ca²⁺-ATPase in hypoxic-reoxygenated cardiomyocytes were attenuated by astragaloside IV treatment. These results suggest that the beneficial effect of astragaloside IV in H/R-induced injury may be related to normalization of SR Ca²⁺ pump expression and, thus, may prevent the depression in SR Ca²⁺ handling.

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Allopurinol modulates reactive oxygen species generation and Ca2+ overload in ischemia-reperfused heart and hypoxia-reoxygenated cardiomyocytes

Cited by 69 publications

References 28 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

Allopurinol preconditioning attenuates renal ischemia/reperfusion injury by inhibiting HMGB1 expression in a rat model

Astragaloside IV Improved Intracellular Calcium Handling in Hypoxia-Reoxygenated Cardiomyocytes via the Sarcoplasmic Reticulum Ca<sup>2+</sup>-ATPase

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