Allopurinol modulates reactive oxygen species generation and Ca 2+ overload in ischemia-reperfused heart and hypoxia-reoxygenated cardiomyocytes

seokmin kang, Soyeon Lim, Heesang Song, Woochul Chang, Sunju Lee, Sang Mee Bae, Ji Hyung Chung, Hakbae Lee, Ho Gyoung Kim, Deok Hyo Yoon, Tae Woong Kim, Yangsoo Jang, Jae Mo Sung, Nam Sik Chung, Ki Chul Hwang

Research output: Contribution to journalArticle

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Abstract

Myocardial oxidative stress and Ca2+ overload induced by ischemia-reperfusion may be involved in the development and progression of myocardial dysfunction in heart failure. Xanthine oxidase, which is capable of producing reactive oxygen species, is considered as a culprit regarding ischemia-reperfusion injury of cardiomyocytes. Even though inhibition of xanthine oxidase by allopurinol in failing hearts improves cardiac performance, the regulatory mechanisms are not known in detail. We therefore hypothesized that allopurinol may prevent the xanthine oxidase-induced reactive oxygen species production and Ca2+ overload, leading to decreased calcium-responsive signaling in myocardial dysfunction. Allopurinol reversed the increased xanthine oxidase activity in ischemia-reperfusion injury of neonatal rat hearts. Hypoxia-reoxygenation injury, which simulates ischemia-reperfusion injury, of neonatal rat cardiomyocytes resulted in activation of xanthine oxidase relative to that of the control, indicating that intracellular xanthine oxidase exists in neonatal rat cardiomyocytes and that hypoxia-reoxygenation induces xanthine oxidase activity. Allopurinol (10 μM) treatment suppressed xanthine oxidase activity induced by hypoxia-reoxygenation injury and the production of reactive oxygen species. Allopurinol also decreased the concentration of intracellular Ca2+ increased by enhanced xanthine oxidase activity. Enhanced xanthine oxidase activity resulted in decreased expression of protein kinase C and sarcoendoplasmic reticulum calcium ATPase and increased the phosphorylation of extracellular signal-regulated protein kinase and p38 kinase. Xanthine oxidase activity was increased in both ischemia-reperfusion-injured rat hearts and hypoxia-reoxygenation-injured cardiomyocytes, leading to reactive oxygen species production and intracellular Ca2+ overload through mechanisms involving p38 kinase and extracellular signal-regulated protein kinase (ERK) via sarcoendoplasmic reticulum calcium ATPase (SERCA) and protein kinase C (PKC). Xanthine oxidase inhibition with allopurinol modulates reactive oxygen species production and intracellular Ca2+ overload in hypoxia-reoxygenation-injured neonatal rat cardiomyocytes.

Original languageEnglish
Pages (from-to)212-219
Number of pages8
JournalEuropean Journal of Pharmacology
Volume535
Issue number1-3
DOIs
Publication statusPublished - 2006 Mar 27

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Allopurinol
Xanthine Oxidase
Cardiac Myocytes
Reactive Oxygen Species
Ischemia
Reperfusion Injury
Reticulum
Calcium-Transporting ATPases
Extracellular Signal-Regulated MAP Kinases
Protein Kinases
Protein Kinase C
Reperfusion
Hypoxia
Phosphotransferases
Calcium Signaling
Wounds and Injuries
Oxidative Stress
Heart Failure
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

kang, seokmin ; Lim, Soyeon ; Song, Heesang ; Chang, Woochul ; Lee, Sunju ; Bae, Sang Mee ; Chung, Ji Hyung ; Lee, Hakbae ; Kim, Ho Gyoung ; Yoon, Deok Hyo ; Kim, Tae Woong ; Jang, Yangsoo ; Sung, Jae Mo ; Chung, Nam Sik ; Hwang, Ki Chul. / Allopurinol modulates reactive oxygen species generation and Ca 2+ overload in ischemia-reperfused heart and hypoxia-reoxygenated cardiomyocytes. In: European Journal of Pharmacology. 2006 ; Vol. 535, No. 1-3. pp. 212-219.
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abstract = "Myocardial oxidative stress and Ca2+ overload induced by ischemia-reperfusion may be involved in the development and progression of myocardial dysfunction in heart failure. Xanthine oxidase, which is capable of producing reactive oxygen species, is considered as a culprit regarding ischemia-reperfusion injury of cardiomyocytes. Even though inhibition of xanthine oxidase by allopurinol in failing hearts improves cardiac performance, the regulatory mechanisms are not known in detail. We therefore hypothesized that allopurinol may prevent the xanthine oxidase-induced reactive oxygen species production and Ca2+ overload, leading to decreased calcium-responsive signaling in myocardial dysfunction. Allopurinol reversed the increased xanthine oxidase activity in ischemia-reperfusion injury of neonatal rat hearts. Hypoxia-reoxygenation injury, which simulates ischemia-reperfusion injury, of neonatal rat cardiomyocytes resulted in activation of xanthine oxidase relative to that of the control, indicating that intracellular xanthine oxidase exists in neonatal rat cardiomyocytes and that hypoxia-reoxygenation induces xanthine oxidase activity. Allopurinol (10 μM) treatment suppressed xanthine oxidase activity induced by hypoxia-reoxygenation injury and the production of reactive oxygen species. Allopurinol also decreased the concentration of intracellular Ca2+ increased by enhanced xanthine oxidase activity. Enhanced xanthine oxidase activity resulted in decreased expression of protein kinase C and sarcoendoplasmic reticulum calcium ATPase and increased the phosphorylation of extracellular signal-regulated protein kinase and p38 kinase. Xanthine oxidase activity was increased in both ischemia-reperfusion-injured rat hearts and hypoxia-reoxygenation-injured cardiomyocytes, leading to reactive oxygen species production and intracellular Ca2+ overload through mechanisms involving p38 kinase and extracellular signal-regulated protein kinase (ERK) via sarcoendoplasmic reticulum calcium ATPase (SERCA) and protein kinase C (PKC). Xanthine oxidase inhibition with allopurinol modulates reactive oxygen species production and intracellular Ca2+ overload in hypoxia-reoxygenation-injured neonatal rat cardiomyocytes.",
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Allopurinol modulates reactive oxygen species generation and Ca 2+ overload in ischemia-reperfused heart and hypoxia-reoxygenated cardiomyocytes. / kang, seokmin; Lim, Soyeon; Song, Heesang; Chang, Woochul; Lee, Sunju; Bae, Sang Mee; Chung, Ji Hyung; Lee, Hakbae; Kim, Ho Gyoung; Yoon, Deok Hyo; Kim, Tae Woong; Jang, Yangsoo; Sung, Jae Mo; Chung, Nam Sik; Hwang, Ki Chul.

In: European Journal of Pharmacology, Vol. 535, No. 1-3, 27.03.2006, p. 212-219.

Research output: Contribution to journalArticle

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AU - kang, seokmin

AU - Lim, Soyeon

AU - Song, Heesang

AU - Chang, Woochul

AU - Lee, Sunju

AU - Bae, Sang Mee

AU - Chung, Ji Hyung

AU - Lee, Hakbae

AU - Kim, Ho Gyoung

AU - Yoon, Deok Hyo

AU - Kim, Tae Woong

AU - Jang, Yangsoo

AU - Sung, Jae Mo

AU - Chung, Nam Sik

AU - Hwang, Ki Chul

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N2 - Myocardial oxidative stress and Ca2+ overload induced by ischemia-reperfusion may be involved in the development and progression of myocardial dysfunction in heart failure. Xanthine oxidase, which is capable of producing reactive oxygen species, is considered as a culprit regarding ischemia-reperfusion injury of cardiomyocytes. Even though inhibition of xanthine oxidase by allopurinol in failing hearts improves cardiac performance, the regulatory mechanisms are not known in detail. We therefore hypothesized that allopurinol may prevent the xanthine oxidase-induced reactive oxygen species production and Ca2+ overload, leading to decreased calcium-responsive signaling in myocardial dysfunction. Allopurinol reversed the increased xanthine oxidase activity in ischemia-reperfusion injury of neonatal rat hearts. Hypoxia-reoxygenation injury, which simulates ischemia-reperfusion injury, of neonatal rat cardiomyocytes resulted in activation of xanthine oxidase relative to that of the control, indicating that intracellular xanthine oxidase exists in neonatal rat cardiomyocytes and that hypoxia-reoxygenation induces xanthine oxidase activity. Allopurinol (10 μM) treatment suppressed xanthine oxidase activity induced by hypoxia-reoxygenation injury and the production of reactive oxygen species. Allopurinol also decreased the concentration of intracellular Ca2+ increased by enhanced xanthine oxidase activity. Enhanced xanthine oxidase activity resulted in decreased expression of protein kinase C and sarcoendoplasmic reticulum calcium ATPase and increased the phosphorylation of extracellular signal-regulated protein kinase and p38 kinase. Xanthine oxidase activity was increased in both ischemia-reperfusion-injured rat hearts and hypoxia-reoxygenation-injured cardiomyocytes, leading to reactive oxygen species production and intracellular Ca2+ overload through mechanisms involving p38 kinase and extracellular signal-regulated protein kinase (ERK) via sarcoendoplasmic reticulum calcium ATPase (SERCA) and protein kinase C (PKC). Xanthine oxidase inhibition with allopurinol modulates reactive oxygen species production and intracellular Ca2+ overload in hypoxia-reoxygenation-injured neonatal rat cardiomyocytes.

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