Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress-Mediated Atrial Remodeling in Alloxan-Induced Diabetes Mellitus Rabbits.
Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress-Mediated Atrial Remodeling in Alloxan-Induced Diabetes Mellitus Rabbits.
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黄嘌呤氧化酶抑制剂别嘌呤醇可预防四氧嘧啶诱发的糖尿病兔氧化应激介导的心房重塑
DOI：
10.1161/jaha.118.008807
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发表时间：
2018-05-02
影响因子：
5.4
通讯作者：
Liu T
中科院分区：
文献类型：
--
作者：
Yang Y;Zhao J;Qiu J;Li J;Liang X;Zhang Z;Zhang X;Fu H;Korantzopoulos P;Letsas KP;Tse G;Li G;Liu T
心房颤动的发病机制包括炎症、氧化应激和钙稳态异常等。在糖尿病（DM）中，增加的氧化应激可能归因于较高的黄嘌呤氧化酶活性。在这项研究中，我们研究了氧化应激和心房电和结构重塑，钙处理异常之间的关系，以及黄嘌呤氧化酶抑制剂别嘌呤醇对这些病理变化的潜在有益作用。将90只兔子随机平均分为3组：对照组、DM组和别嘌呤醇治疗DM组。在体内进行超声心动图和血流动力学评估。检测氧化应激和心房纤维化的血清和组织标志物，包括蛋白表达。Masson三色染色评价心房间质纤维化。使用电压钳技术从分离的左心房心肌细胞测量ICaL。共聚焦显微镜用于检测细胞内钙瞬变。Western blotting分析Ca2+处理蛋白的表达。分析线粒体相关蛋白作为线粒体功能的标志物。与对照组相比，DM组左心室肥厚，心房间质纤维化、氧化应激和纤维化指标、ICaL和细胞内钙瞬变增加，心房颤动发生率增高。别嘌呤醇治疗可缓解这些异常。别嘌呤醇通过其抗氧化作用，减少由DM相关氧化应激增加诱导的心房机械、结构、离子通道重塑和线粒体合成异常。
There are several mechanisms, including inflammation, oxidative stress and abnormal calcium homeostasis, involved in the pathogenesis of atrial fibrillation. In diabetes mellitus (DM), increased oxidative stress may be attributable to higher xanthine oxidase activity. In this study, we examined the relationship between oxidative stress and atrial electrical and structural remodeling, and calcium handling abnormalities, and the potential beneficial effects of the xanthine oxidase inhibitor allopurinol upon these pathological changes. Ninety rabbits were randomly and equally divided into 3 groups: control, DM, and allopurinol‐treated DM group. Echocardiographic and hemodynamic assessments were performed in vivo. Serum and tissue markers of oxidative stress and atrial fibrosis, including the protein expression were examined. Atrial interstitial fibrosis was evaluated by Masson trichrome staining. ICaL was measured from isolated left atrial cardiomyocytes using voltage‐clamp techniques. Confocal microscopy was used to detect intracellular calcium transients. The Ca2+ handling protein expression was analyzed by Western blotting. Mitochondrial‐related proteins were analyzed as markers of mitochondrial function. Compared with the control group, rabbits with DM showed left ventricular hypertrophy, increased atrial interstitial fibrosis, oxidative stress and fibrosis markers, ICaL and intracellular calcium transient, and atrial fibrillation inducibility. These abnormalities were alleviated by allopurinol treatment. Allopurinol, via its antioxidant effects, reduces atrial mechanical, structural, ion channel remodeling and mitochondrial synthesis abnormalities induced by DM‐related increases in oxidative stress.