Electron transport chain defects in heart failure.
Electron transport chain defects in heart failure.
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DOI：
10.1023/a:1015372407647
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发表时间：
2002-04-01
影响因子：
4.6
通讯作者：
Miro, Oscar
中科院分区：
文献类型：
--
作者：
Casademont, Jordi;Miro, Oscar
近年来，心脏代谢紊乱在导致心力衰竭时心室扩张和功能障碍的机制中发挥作用的可能性引起了广泛关注。电子传递链由一系列位于线粒体内膜的多聚体蛋白复合物组成，其基因分布在核DNA和线粒体DNA上。它的正常功能是必不可少的，为心脏功能提供能量。许多研究描述了扩张型心肌病中编码电子传递链（ETC）的线粒体DNA基因异常。在某些情况下，心力衰竭是线粒体脑肌病特征性的其他多系统表现中的一种或多或少相关的症状，是可归因于原发性线粒体疾病的心力衰竭。在特发性扩张型心肌病（IDC）的情况下，许多线粒体异常也被描述使用组织学，生物化学或分子研究。这些发现的重要性正在讨论之中。所描述的线粒体异常的巨大变异性促使人们提出线粒体功能障碍可能是IDC的继发现象，而不是原发现象。在对这些发现的其他可能的解释中，已经假设存在由于自由基过量而增加的氧化损伤。在这种情况下，ETC功能障碍可能是一个后果，但也是一个原因的存在增加的自由基损伤。独立于其起源，ETC功能障碍可能导致心力衰竭的持续和恶化。如果这一假说（尚待证实）是肯定的，那么调节心脏代谢可能是治疗IDC的一种有趣方法。导致心力衰竭时心室扩张和功能障碍的确切机制至今仍知之甚少。已经对细胞毒性损伤、病毒感染、免疫异常、收缩蛋白缺陷、缺血因素和家族性疾病等情况进行了深入研究[1]。可能是几种机制联合收割机共同产生心力衰竭的临床综合征。近年来，能量代谢紊乱（单独或与其他上述因素联合）可能在易感患者心力衰竭的发展中发挥作用的可能性引起了广泛关注。本文就线粒体功能在衰竭心肌中的作用作一综述。我们将讨论限制在心力衰竭，其中变力性状态受损导致收缩期收缩减弱（即所谓的收缩性心力衰竭）。特发性扩张型心肌病（IDC）是所讨论的条件的原型。心肌收缩缺陷是由于慢性过度工作负荷引起的其他情况（即，高血压、瓣膜病或先天性心脏病），和其中主要异常涉及心室松弛受损的状态（即舒张性心力衰竭），以及电子传递链外的线粒体缺陷（即，Krebs循环或脂肪酸的β-氧化的缺陷）仅在情况下进行。
In recent years, the possibility that disorders of cardiac metabolism play a role in the mechanisms that lead to ventricular dilatation and dysfunction in heart failure has attracted much attention. Electron transport chain is constituted by a series of multimeric protein complexes, located in the inner mitochondrial membranes, whose genes are distributed over both nuclear and mitochondrial DNA. Its normal function is essential to provide the energy for cardiac function. Many studies have described abnormalities in mitochondrial DNA genes encoding for electron transport chain (ETC) in dilated cardiomyopathies. In some cases, heart failure is one more or less relevant symptom among other multisystem manifestations characteristic of mitochondrial encephalomyopathies, being heart failure imputable to a primary mitochondrial disease. In the case of idiopathic dilated cardiomyopathies (IDC), many mitochondrial abnormalities have also been described using hystological, biochemical or molecular studies. The importance of such findings is under debate. The great variability in the mitochondrial abnormalities described has prompted the proposal that mitochondrial dysfunction could be a secondary phenomenon in IDC, and not a primary one. Among other possible explanations for such findings, the presence of an increased oxidative damage due to a free radical excess has been postulated. In this setting, the dysfunction of ETC could be a consequence, but also a cause of the presence of an increased free radical damage. Independently of its origin, ETC dysfunction may contribute to the persistence and worsening of heart failure. If this hypothesis, still to be proven, was certain, the modulation of cardiac metabolism could be an interesting approach to treat IDC. The precise mechanisms that lead to ventricular dilatation and dysfunction in heart failure are still nowadays poorly understood. Circumstances such as cytotoxic insults, viral infections, immune abnormalities, contractile protein defects, ischemic factors and familial conditions have been thoroughly investigated [1]. It is possible that several mechanisms combine to produce the clinical syndrome of heart failure. In recent years the possibility that disorders of energy metabolism, either isolated or in combination with the other aforementioned factors, may play a role in the development of heart failure in susceptible patients has attracted much attention. The present paper reviews the current knowledge on mitochondrial function in the failing myocardium. We restrain our discussion to heart failure where an impaired inotropic state leads to a weakened systolic contraction (i.e. the so-called systolic heart failure). Idiopathic dilated cardiomyopathy (IDC) is the prototype of the conditions under discussion. Other circumstances where a defect in myocardial contraction is due to a chronic excessive work load (i.e., hypertension, valvular or congenital heart diseases), and states in which the principal abnormality involves impaired relaxation of the ventricle (i.e. diastolic heart failure), as well as mitochondrial defects outside the electron transport chain (i.e., defects in Krebs cycle or beta-oxidation of fatty acids) are only approached circumstantially.