羟嘌呤醇对衰竭心肌蛋白氧化和心肌收缩力的长期效果

›› 2010, Vol. 30 ›› Issue (2): 174-.

羟嘌呤醇对衰竭心肌蛋白氧化和心肌收缩力的长期效果

谭震^1,2, 张治¹, 戴秋艳¹, 张建军¹, 高卫东²

1. 上海交通大学第一人民医院心内科, 上海 200080；2. 约翰霍普金斯大学医学院麻醉和重症监护科, 巴尔第摩 21287, 美国

出版日期:2010-02-25 发布日期:2010-02-25
通讯作者: 张建军, 电子信箱: tanzzj@hotmail.com。
作者简介:谭震（1979—）, 男, 博士生；电子信箱: zhentanhrb@gmail.com。
基金资助:
国家建设高水平大学公派联合培养研究生项目

Long-term effects of oxypurinol on oxidative modification of actin and myocardial contractility in mice with heart failure

TAN Zhen^1,2, ZHANG Zhi¹, DAI Qiu-yan¹, ZHANG Jian-jun¹, GAO Wei-dong²

1. Department of Cardiology, The First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, China；2. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore 21287, USA

Online:2010-02-25 Published:2010-02-25
Supported by:
Joint Training Program by State Scholarship Fund

摘要/Abstract

摘要：

目的研究黄嘌呤氧化酶（XO）抑制剂——羟嘌呤醇（Oxy）增强缺血后心力衰竭心肌收缩力的长期效果，并初步探讨其作用机制。方法将120只SV120小鼠随机分为心肌梗死（MI）对照组、假手术组和Oxy治疗组。通过结扎冠状动脉左前降支（LAD）建立小鼠缺血后心力衰竭模型。Oxy治疗组口服1 mmol/L Oxy。9~11个月后，对三组小鼠进行心脏超声检查；取右心室束状肌分析其心肌兴奋-收缩耦联的变化。应用激光光栅衍射测定肌节长度；应用离子渗透微注射法向样本心肌细胞内注入Fura-2荧光染料，测量心肌细胞质内游离Ca²⁺浓度（[Ca²⁺]_i）；通过应用ryanodine和增加刺激频率的方法使心肌达到强直收缩，即心肌纤维与Ca²⁺的相互作用处于稳定状态，分析在稳定状态下心肌收缩力-细胞内钙关系；应用Western blotting测定肌丝蛋白的氧化情况。结果长期口服Oxy能明显改善心力衰竭小鼠的心脏收缩功能，减小室壁厚度；明显改善心肌细胞的兴奋-收缩耦联过程，有效地增强心肌收缩力，显著提高稳态时心肌细胞钙激活的最大收缩力（F_max）。Western blotting检测显示，与MI对照组心肌肌丝蛋白相比，Oxy治疗组中的肌动蛋白氧化修饰受到明显抑制。结论长期服用Oxy能够有效改善衰竭心肌的工作状态，改善/促进兴奋-收缩耦联过程，增强心肌收缩力。这种长期作用的机制是抑制心肌肌丝中肌动蛋白的氧化修饰，从而增强肌丝对钙的敏感性，增加收缩力。Oxy由于对[Ca²⁺]_i的增加较小，能够减轻细胞内Ca²⁺负担及其所带来的负作用，具有更好的临床应用前景。

关键词: 羟嘌呤醇, 心力衰竭, 心肌收缩力, 氧化修饰, 稳态力钙关系

Abstract:

Objective To investigate the long-term effects of xanthine oxidase inhibitor, oxypurinol on myocardial contractility of post-ischemic heart failure in mice, and explore the underlying mechanism. Methods One hundred and twenty SV120 mice were randomly assigned into myocardial infarction control group, sham operation group and Oxy treatment group. Post-ischemic heart failure were induced by left anterior descending coronary artery ligation in myocardial infarction control group and Oxy treatment group, and mice in Oxy treatment group and sham operation group were orally administered with 0.5 mmol/L Oxy each day. Nine to eleven months after treatment, echocardiography was performed in all groups. Trabeculae from the right ventricle of mice were dissected for assessment of changes in excitation-contraction coupling. Sarcomere length was measured by laser diffraction. Intracellular free Ca²⁺ concentration ([Ca²⁺]_i) was detected with fluorescent dye Fura-2, which was microinjected iontophoretically into cells. Steady-state force-[Ca²⁺]_i was achieved by addition of ryanodine and increasing the stimulus frequency to induce tetanization, and the relationship between myocardial contractility and intracellular Ca²⁺ transients was analysed. Besides, Western blotting was performed to determine the oxidation of myofilament proteins. Results Long-term oral administration of oxypurinol significantly improved myocardial contraction function and reduced ventricular wall thickness. Programming of excitation-contraction coupling was significantly improved, and maximal Ca²⁺ activated force (F_max) in steady-state was also significantly increased. Western blotting revealed the oxidative modification of actin in mice of Oxy treatment group was significantly inhibited compared with that of myocardial infarction control group. Conclusion Long-term treatment with Oxy improves the cardiac contraction function and boosts the cardiac force dramatically in post-ischemia heart failure. The increase in contraction is the result of increased myofilament Ca²⁺ responsiveness. Thus, antioxidant oxypurinol, by preventing oxidative damage to contractile proteins, can augment contraction with little changes in [Ca²⁺]_i, represents new class of inotropic agents with advantages of reducing Ca²⁺ overload, and offers new promises in management of heart failure in the future.

Key words: oxypurinol, heart failure, myocardial contraction, oxidative modification, steady-state force-[Ca²⁺]_i relation

谭震, 张治, 戴秋艳, 等. 羟嘌呤醇对衰竭心肌蛋白氧化和心肌收缩力的长期效果[J]. , 2010, 30(2): 174-.

TAN Zhen, ZHANG Zhi, DAI Qiu-yan, et al. Long-term effects of oxypurinol on oxidative modification of actin and myocardial contractility in mice with heart failure[J]. , 2010, 30(2): 174-.

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