Allopurinol modulates reactive oxygen species generation and Ca2+ overload in ischemia-reperfused heart and hypoxia-reoxygenated cardiomyocytes
Allopurinol modulates reactive oxygen species generation and Ca2+ overload in ischemia-reperfused heart and hypoxia-reoxygenated cardiomyocytes
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DOI：
10.1016/j.ejphar.2006.01.013
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发表时间：
2006-03-27
影响因子：
5
通讯作者：
Hwang, KC
中科院分区：
文献类型：
--
作者：
Kang, SM;Lim, S;Hwang, KC
缺血再灌注引起的心肌氧化应激和钙超载可能参与了心力衰竭心肌功能障碍的发生和发展。黄嘌呤氧化酶能够产生活性氧，被认为是心肌细胞缺血再灌注损伤的罪魁祸首。尽管在衰竭心脏中别嘌呤醇抑制黄嘌呤氧化酶可改善心脏性能，但其调节机制尚不清楚。因此，我们假设别嘌呤醇可能会阻止黄嘌呤氧化酶诱导的活性氧产生和Ca 2+超载，导致心肌功能障碍中钙响应信号的减少。别嘌呤醇逆转新生大鼠心脏缺血再灌注损伤中黄嘌呤氧化酶活性的升高。缺氧-复氧损伤，模拟缺血-再灌注损伤，新生大鼠心肌细胞的黄嘌呤氧化酶的激活相对于对照组，表明细胞内的黄嘌呤氧化酶存在于新生大鼠心肌细胞和缺氧-复氧诱导黄嘌呤氧化酶的活性。别嘌呤醇（10 μ M）治疗抑制黄嘌呤氧化酶活性诱导的缺氧-复氧损伤和活性氧的产生。别嘌呤醇也降低了细胞内Ca ~（2+）的浓度增加黄嘌呤氧化酶的活性。黄嘌呤氧化酶活性增强导致蛋白激酶C和肌内质网钙ATP酶表达降低，细胞外信号调节蛋白激酶和p38激酶磷酸化增加。黄嘌呤氧化酶活性在缺血-再灌注损伤和缺氧-再给氧损伤的心肌细胞中均升高，通过p38激酶和细胞外信号调节蛋白激酶（ERK）介导的肌内质网钙ATP酶（SERCA）和蛋白激酶C（PKC）机制导致活性氧产生和细胞内钙超载。黄嘌呤氧化酶抑制与别嘌呤醇调节活性氧产生和细胞内钙超载缺氧-复氧损伤的新生大鼠心肌细胞。(c)2006 Elsevier B. V.保留所有权利。
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 mu M) 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. (c) 2006 Elsevier B.V. All rights reserved.