Redox Modulation of Cardiac Electrical Activity
Redox Modulation of Cardiac Electrical Activity
复制标题
心脏电活动的氧化还原调节
DOI：
10.1046/j.1540-8167.2001.00183.x
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发表时间：
2001
影响因子：
2.7
通讯作者：
D. Wagoner
中科院分区：
文献类型：
--
作者：
D. Wagoner
心力衰竭常伴有QT间期延长，并与室性心律失常的发生率增加有关。QT间期延长和心律失常发生的机制是复杂的，可能既反映了特异性离子电流密度的变化，也反映了不应期离散度的增加。几项研究记录了心力衰竭患者心室心外膜瞬时外向K 1电流（Ito）的减少1，2以及起搏和/或心力衰竭动物模型。3这些研究检测到Kv 4.3亚基的转录和表达减少，该亚基被认为是Ito的基础。因此，离子通道表达的转录控制显然是可以调节动作电位持续时间（从而调节QT间期）的一种机制。然而，越来越明显的是，这并不是唯一的机制。心力衰竭患者患有一系列电生理、机械和代谢异常。这似乎是直观的，可能有一些不同的病理表现之间的基本关系的心力衰竭。例如，心力衰竭和/或动脉粥样硬化患者的血浆同型半胱氨酸水平经常升高，而高同型半胱氨酸血症是死亡率增加的风险因素。4 Pacher等人5最近使用微电极技术证明，急性给予病理生理相关浓度的同型半胱氨酸可降低大鼠心室小梁的上行速度并延长动作电位时程。本研究并未试图确定由同型半胱氨酸调节的离子电流，尽管人们可能合理地推测钠电流、钙电流和/或钾电流作为该效应的潜在介质的作用。在本期杂志中，Shontz等人6介绍了一项电压钳研究，其中他们探索了同型半胱氨酸对大鼠心脏复极化钾电流的影响。他们证明，用高半胱氨酸或主要循环氧化形式高胱氨酸灌注大鼠心室肌细胞，在5至10分钟内显著降低Ito的电流密度。该效应对Ito具有特异性，因为平台电流Iss不受影响，IK1几乎不受影响。电流降低的相对缓慢的开始，以及洗脱后无法恢复电流，表明该作用不是通过直接通道阻断介导的，或者根据其他实验，依赖于蛋白激酶C激活。相反，作者得出结论，同型半胱氨酸对Ito的抑制可能是通过改变细胞氧化还原状态，通过化合物与通道亚基之一上的游离半胱氨酸硫醇的相互作用介导的。在检查与急性缺血发作相关的电生理事件的研究中，细胞氧化还原状态的重要作用也在不断发展。由于L型钙电流ICa的抑制，心室心肌缺血区域的动作电位通常变得更短且更三角形。最近的研究表明，除了缺血期间pH值改变的直接影响外，人类心脏钙通道还可以“感知”pO2的降低。8这种效应也是通过改变细胞内氧化还原状态介导的，这种状态导致L型Ca通道α 1c亚基C末端特定半胱氨酸残基上巯基的修饰。9氧化还原调节对心脏钠通道功能的影响仍有待探索，但Pacher等人的研究5表明，响应于巯基修饰的INa减少并不令人惊讶。显然，离子通道存在于代谢活跃的细胞的连接中。细胞氧化还原状态反映了氧化和还原当量的净平衡。这种平衡可能会在心肌细胞中向更氧化的状态转移，这些心肌细胞面临着主要细胞还原当量（还原型谷胱甘肽等）的消耗增加。有趣的是，在大鼠冠状动脉结扎心力衰竭模型（也伴随着Ito的减少）中，Rozanski等人10最近报告称，用还原型谷胱甘肽或N-乙酰半胱氨酸孵育衰竭的心室肌细胞（一种谷胱甘肽前体）在孵育2至3小时内将Ito恢复到正常水平，这证实了这一概念。心脏离子通道受其代谢环境动态调节的反复观察可能对理解与心力衰竭和其他心脏疾病相关的心律失常的电生理异常具有根本重要性。例如，心房颤动还与显着的电生理重塑相关11，并与一系列潜在的代谢异常相关（糖尿病、高血压、心力衰竭、甲状腺疾病、慢性阻塞性肺疾病J Cardiovasc Electrophysiol，第12卷，第12页）。183 - 184，2001年2月
Heart failure frequently is accompanied by QT prolongation and is associated with an increased incidence of ventricular arrhythmias. The mechanisms responsible for QT prolongation and arrhythmogenesis are complex and may re ect both changes in the density of speci c ionic currents and an increase in the dispersion of refractoriness. Several studies documented a reduction in the transient outward K 1 current (Ito) in the ventricular epicardium of heart failure patients1 ,2 and in animal models of pacing and/or heart failure.3 These studies detected reduced transcription and expression of the Kv4.3 subunit, the primary subunit thought to underlie Ito. Thus, transcriptional control of ion channel expression is clearly one mechanism by which action potential duration (and thereby the QT interval) can be modulated. However, it is becoming evident that this is not the only mechanism. Heart failure patients suffer from a spectrum of electrophysiologic,mechanical, and metabolic abnormalities. It seems intuitive that there may be fundamental relationships between some of the different pathologic manifestations of heart failure. For instance, patients with heart failure and/or atherosclerosis frequently have elevated plasma homocysteine levels, and hyperhomocysteinemia is a risk factor for increased mortality.4 Using microelectrode techniques, Pacher et al.5 recently demonstrated that acute administration of homocysteine at pathophysiologically relevant concentrations decreased the upstroke velocity and prolonged action potential duration in rat ventricular trabeculae. This study did not attempt to identify the ionic currents that were modulated by homocysteine, although one might reasonably speculate upon roles for sodium currents, calcium currents, and/or potassium currents as potential mediators of this effect. In this issue of the Journal, Shontz et al.6 present a voltage-clamp study in which they explore the effects of homocysteine on the potassium currents responsible for repolarization in the rat heart. They demonstrate that superfusion of rat ventricular myocytes with either homocysteine or the major circulating oxidized form, homocystine, signi cantly reduced the current density of Ito within 5 to 10 minutes. The effect was speci c for Ito, because the plateau current Iss was unaffected and IK1 was little affected. The relatively slow onset of the reduction in current, together with an inability to restore the current upon washout, suggested that the effect was not mediated via direct channel blockade, or, from other experiments, dependent on protein kinase C activation. Rather, the authors conclude that suppression of Ito by homocysteine is likely mediated by an interaction of the compound with free cysteine thiols on one of the channel subunits, by altering the cellular redox state. An important role for cellular redox state also is evolving in studies examining the electrophysiologic events associated with acute episodes of ischemia. The action potential in ischemic regions of the ventricular myocardium typically becomes shorter and more triangular, due to inhibition of the L-type calcium current ICa. Recent studies showed that, in addition to the direct effects of altered pH during ischemia, the human cardiac calcium channel can “sense” a reduction in pO2. ,8 This effect also is mediated via an altered intracellular redox state that leads to a modi cation of thiol groups on speci c cysteine residues in the C-terminus of the a 1csubunit of the L-type Ca channel.9 The impact of redox modulation on the function of cardiac sodium channels remains to be explored, but the study of Pacher et al.5 suggests that a decrement in INa in response to thiol modi cation would not be surprising. Clearly, ion channels exist within the con nes of metabolically active cells. Cellular redox state re ects the net balance of oxidizing and reducing equivalents. This balance is likely shifted toward a more oxidized state in myocytes from hearts that are faced with increased consumption of the major cellular reducing equivalents (reduced glutathione, etc.). Lending credence to this concept, it is intriguing to note that in the rat coronary ligation heart failure model (also accompanied by a reduction in Ito), Rozanski et al.10 recently reported that incubation of the failing ventricular myocytes with either reduced glutathione or N-acetylcysteine (a glutathione precursor) restored Ito to normal levels within 2 to 3 hours of incubation. The recurring observation that cardiac ion channels are dynamically modulated by their metabolic environment probably is of fundamental importance in understanding the electrophysiologic abnormalities associated with heart failure and other cardiac diseases with associated arrhythmias. For example, atrial brillation also is associated with signi cant electrophysiologic remodeling1 1 and is associated with an array of underlying metabolic abnormalities (diabetes, hypertension, heart failure, thyroid disorders, chronic obstructive pulmonary J Cardiovasc Electrophysiol, Vol. 12, pp. 183-184, February 2001
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影响因子：
37.8
作者：
Yu, HG;McKinnon, D;Rosen, MR
通讯作者：
Rosen, MR
影响因子：
9.3
作者：
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通讯作者：
D. Jacobsen
影响因子：
37.8
作者：
Kääb, S;Dixon, J;Tomaselli, GF
通讯作者：
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影响因子：
5
作者：
Van Wagoner, DR;Nerbonne, JM
通讯作者：
Nerbonne, JM