Febuxostat pretreatment attenuates myocardial ischemia/reperfusion injury via mitochondrial apoptosis.
Febuxostat pretreatment attenuates myocardial ischemia/reperfusion injury via mitochondrial apoptosis.
复制标题
非布索坦预处理通过线粒体凋亡减轻心肌缺血/再灌注损伤
DOI：
10.1186/s12967-015-0578-x
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发表时间：
2015-07-02
影响因子：
7.4
通讯作者：
Yang P
中科院分区：
文献类型：
--
作者：
Wang S;Li Y;Song X;Wang X;Zhao C;Chen A;Yang P
非布司他是一种选择性黄嘌呤氧化酶（XO）抑制剂。XO是心肌缺血/再灌注（I/R）损伤过程中活性氧（ROS）的重要来源。XO的抑制在I/R损伤中是治疗有效的。有证据表明，非布司他通过直接清除ROS发挥抗氧化作用。本研究旨在探讨非布索坦对心肌I/R损伤及其机制的影响。方法采用小鼠心肌I/R损伤模型和新生大鼠心肌细胞（NRC）缺氧/复氧（H/R）损伤模型。将小鼠随机分为五组：分别为假手术组、I/R（I/R +溶媒）组、I/R + FEB（I/R +非布司他）组、AL + I/R（I/R +别嘌呤醇）组和FEB（非布司他）组。将I/R + FEB小鼠用非布司他（5 mg/kg; i. p.）I/R前24和1 h。NRC在暴露于缺氧3 h后再复氧3 h前24 h和1 h接受非布司他（1和10 µM）。检测心功能、心肌梗死面积、血清肌酸激酶（CK）、乳酸脱氢酶（LDH）水平及心肌细胞凋亡指数（AI），以探讨非布索坦对心肌I/R损伤的影响。采用MTT法、LDH漏出法和末端脱氧核苷酸转移酶缺口末端标记法（TUNEL）检测NRCs缺氧/再灌注（H/R）损伤。结果心肌I/R可导致心肌梗死面积、血清CK和LDH水平、细胞死亡和AI升高，细胞色素c、Caspase酶活性和Bcl-2蛋白水平升高。此外，I/R降低了心脏功能。非布司他和别嘌呤醇预处理显著减弱了这些变化，尤其是非布司他。非布司他还保护心肌I/R后的线粒体结构，抑制H/R诱导的ROS产生，稳定Δ Km，减轻线粒体细胞色素C的胞质易位，抑制caspase-3和-9的活化，结论：本研究表明，非布司他预处理通过抑制线粒体膜电位，介导心肌保护作用，对抗I/R和H/R损伤。依赖性凋亡
BackgroundFebuxostat is a selective inhibitor of xanthine oxidase (XO). XO is a critical source of reactive oxygen species (ROS) during myocardial ischemia/reperfusion (I/R) injury. Inhibition of XO is therapeutically effective in I/R injury. Evidence suggests that febuxostat exerts antioxidant effects by directly scavenging ROS. The present study was performed to investigate the effects of febuxostat on myocardial I/R injury and its underlying mechanisms.MethodsWe utilized an in vivo mouse model of myocardial I/R injury and an in vitro neonatal rat cardiomyocyte (NRC) model of hypoxia/reoxygenation (H/R) injury. Mice were randomized into five groups: Sham, I/R (I/R + Vehicle), I/R + FEB (I/R + febuxostat), AL + I/R (I/R + allopurinol) and FEB (febuxostat), respectively. The I/R + FEB mice were pretreated with febuxostat (5 mg/kg; i.p.) 24 and 1 h prior to I/R. NRCs received febuxostat (1 and 10 µM) at 24 and 1 h before exposure to hypoxia for 3 h followed by reoxygenation for 3 h. Cardiac function, myocardial infarct size, serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH), and myocardial apoptotic index (AI) were measured in order to ascertain the effects of febuxostat on myocardial I/R injury. Hypoxia/reperfusion (H/R) injury in NRCs was examined using MTT, LDH leakage assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The underlying mechanisms were determined by measuring ROS production, mitochondrial membrane potential (ΔΨm), and expression of cytochrome c, cleaved caspases as well as Bcl-2 protein levels.ResultsMyocardial I/R led to an elevation in the myocardial infarct size, serum levels of CK and LDH, cell death and AI. Furthermore, I/R reduced cardiac function. These changes were significantly attenuated by pretreatment with febuxostat and allopurinol, especially by febuxostat. Febuxostat also protected the mitochondrial structure following myocardial I/R, inhibited H/R-induced ROS generation, stabilized the ΔΨm, alleviated cytosolic translocation of mitochondrial cytochrome C, inhibited activation of caspase-3 and -9, upregulated antiapoptotic proteins and downregulated proapoptotic proteins.ConclusionsThis study revealed that febuxostat pretreatment mediates the cardioprotective effects against I/R and H/R injury by inhibiting mitochondrial-dependent apoptosis.
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DOI：
10.1016/b978-0-12-394309-5.00006-7
发表时间：
2012
影响因子：
--
作者：
Kalogeris, Theodore;Baines, Christopher P.;Krenz, Maike;Korthuis, Ronald J.
通讯作者：
Korthuis, Ronald J.
影响因子：
1.7
作者：
Webster KA
通讯作者：
Webster KA
DOI：
10.1016/j.bbrc.2006.08.140
发表时间：
2006-10-27
影响因子：
3.1
作者：
Lee, Woo-Yong;Lee, Sun-Mee
通讯作者：
Lee, Sun-Mee
影响因子：
5
作者：
Kang, SM;Lim, S;Hwang, KC
通讯作者：
Hwang, KC
影响因子：
10.8
作者：
Ha, Tuanzhu;Hua, Fang;Li, Chuanfu
通讯作者：
Li, Chuanfu