Skeletal muscle myofibrillar protein oxidation in heart failure and the protective effect of Carvedilol
Skeletal muscle myofibrillar protein oxidation in heart failure and the protective effect of Carvedilol
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DOI：
10.1016/j.yjmcc.2005.02.023
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发表时间：
2005-05-01
影响因子：
5
通讯作者：
Vescovo, G
中科院分区：
文献类型：
--
作者：
Dalla Libera, L;Ravara, B;Vescovo, G
心力衰竭的特点是运动耐受性有限，骨骼肌肌病萎缩并向快纤维转移。促炎细胞因子升高和自由基产生过度的炎症状态会加重肌肉损伤。在一种成熟的心力衰竭模型中，我们发现，单缬氨酸治疗大鼠，CHF伴随着骨骼肌肌动蛋白、原肌球蛋白和肌球蛋白的氧化，这进一步抑制了肌肉功能和运动能力。我们还测试了卡维地洛的有效性，卡维地洛是一种非选择性β (1)- β(2)受体阻滞剂，已广泛用于临床试验，以提高中重度CHF大鼠的运动耐量和降低死亡率，防止CHF大鼠收缩蛋白氧化。作为比较，我们使用比索洛尔一种β(1)选择性剂，没有已知的抗氧化性能。氧印迹分析表明，每天2mg /kg剂量的卡维地洛能够阻止肌原纤维蛋白氧化，而0.1 mg/kg剂量的比索洛尔仅能部分阻止肌原纤维蛋白氧化。卡维地洛改善孤立肌肉的发力，而比索洛尔则没有。在COMET试验之后，卡维地洛的抗氧化能力被认为是使该药优于其他选择性β受体阻滞剂治疗CHF的机制之一。卡维地洛优越的原因之一可能是对骨骼肌的作用，减少收缩蛋白过氧化，改善肌肉功能，提高运动耐量。抑制活性氧（ROS）的产生和促炎细胞因子也可能导致肌肉消耗减少，这是导致运动耐量恶化的另一个因素。(C) 2005 Elsevier Ltd版权所有。
Heart failure is characterized by limited exercise tolerance and by a skeletal muscle myopathy with atrophy and shift toward fast fibres. An inflammatory status with elevated pro-inflammatory cytokines and exaggerated free radicals production, can worsen muscle damage. In a well established model of heart failure, the monocrotaline treated rat, we show that CHF is accompanied by oxidation of the skeletal muscle actin, tropomyosin and myosin, which further depresses muscle function and exercise capacity. We have also tested the efficacy of Carvedilol, a non-selective beta(1)-beta(2)-blocker, which has been widely used in clinical trials to improve exercise tolerance and reduce mortality in moderate and severe CHF, in preventing contractile protein oxidation in CHF rats. As comparison we used Bisoprolol a beta(1) selective agent, without known anti-oxidative properties. Carvedilol at the dose of 2 mg/kg per day was able to prevent the myofibrillar protein oxidation, while Bisoprolol (0.1 mg/kg) did it only partially, as demonstrated by the oxyblot analysis. While Carvedilol improved force production on isolated muscles, Bisoprolol did not. After the COMET trial, the anti-oxidative capacity of Carvedilol has been invoked as one of the mechanism that makes this drug superior to other selective beta-blockers in the treatment of CHF. One of the reason of Carvedilol superiority could be the effect on skeletal muscle with reduction of contractile protein peroxidation, amelioration of muscle function and improvement of exercise tolerance. Inhibition of reactive oxygen species (ROS) production, and of pro-inflammatory cytokines may also lead to a decreased muscle wastage, another factor contributing to worsening of exercise tolerance. (C) 2005 Elsevier Ltd. All rights reserved.