Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China.
First Department of Cardiology, University of Ioannina Medical School, Ioannina, Greece.
J Am Heart Assoc. 2018 May 2;7(10):e008807. doi: 10.1161/JAHA.118.008807.
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. I was measured from isolated left atrial cardiomyocytes using voltage-clamp techniques. Confocal microscopy was used to detect intracellular calcium transients. The Ca 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, I 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.
多种机制参与到心房颤动的发病机制中，包括炎症、氧化应激和钙稳态异常。在糖尿病（DM）中，氧化应激增加可能归因于黄嘌呤氧化酶活性升高。在这项研究中，我们研究了氧化应激与心房电重构和结构重构以及钙处理异常之间的关系，以及黄嘌呤氧化酶抑制剂别嘌醇对这些病理变化的潜在有益作用。
90 只兔子被随机均分为 3 组：对照组、DM 组和别嘌醇治疗的 DM 组。进行了体内超声心动图和血流动力学评估。检测了血清和组织氧化应激和心房纤维化的标志物，包括蛋白表达。用 Masson 三色染色评估心房间质纤维化。使用电压钳技术从分离的左心房心肌细胞中测量 I。通过共聚焦显微镜检测细胞内钙瞬变。通过 Western 印迹分析 Ca 处理蛋白表达。线粒体相关蛋白被分析为线粒体功能的标志物。与对照组相比，DM 组兔子出现左心室肥厚、心房间质纤维化增加、氧化应激和纤维化标志物增加、I 和细胞内钙瞬变增加以及心房颤动易感性。别嘌醇治疗减轻了这些异常。
别嘌醇通过其抗氧化作用，减轻了由 DM 相关氧化应激增加引起的心房机械、结构、离子通道重构和线粒体合成异常。
