When the heart sleeps... is the vagus resetting the myocardial 'redox clock'?
When the heart sleeps... is the vagus resetting the myocardial 'redox clock'?
复制标题
当心脏睡觉时……迷走神经会重置心肌“氧化还原时钟”吗？
DOI：
10.1093/cvr/cvn009
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发表时间：
2008
影响因子：
10.8
通讯作者：
Paolocci,Nazareno
中科院分区：
文献类型：
--
作者：
Vecoli,Cecilia;Paolocci,Nazareno
活性氧 (ROS) 是充血性心力衰竭 (CHF) 演变过程中的主要参与者，1 是一种神经内分泌疾病，过量的 ROS 信号传导会导致交感传出纤维过度激活。 2 交感神经流出增强有利于心律失常、心肌重塑/功能障碍和过早死亡（图 1），因此具有发病和预后意义。然而，自主神经系统（ANS）的交感“臂”不仅是ROS的“受害者”，而且还是ROS引起的进一步心肌损伤的“刽子手”。事实上，儿茶酚胺和其他肥大剂（例如血清素、血管紧张素 II 和内皮素-1）的溢出可能会通过其自身增强的分解代谢和/或 ROS 诱导的线粒体释放 ROS 来放大氧化应激，从而引发细胞凋亡和细胞死亡。然而，围绕 CHF 中 ANS-ROS 的“双义”关系，仍有许多未知因素。一是副交感神经（迷走神经）成分的作用。迷走神经刺激 (VNS) 可以限制狗致命性室性心律失常的频率，3 并且可以减轻大鼠的心脏重塑并提高生存率。 4 然而，后者的机制仍然难以捉摸。在最新一期的《心血管研究》中，Ttsutsumi 等人。图5显示VNS使患有CHF的梗塞小鼠体内电子自旋共振(ESR)信号衰减率正常化。这种转变与羟基自由基 († OH) 的生成成正比，这在 CHF 模型中通常会发生变化。 6 Tiron 或二甲基硫脲（分别是超氧化物和† OH 清除剂）等抗氧化剂模仿了 VNS 的保护作用，进一步支持了 VNS 减弱 ROS 产生的概念。这种作用被硫酸阿托品抑制，表明 M2 毒蕈碱受体参与其中。但 VNS-M2 如何减少这些衰竭心脏中过量的 ROS 生成呢？在这里，作者记录了连接前和连接后的胆碱能作用，以抑制“去甲肾上腺素 (NE)-ROS 轴”。在分离的心肌细胞中，b 受体介导的 ROS 产生通过与乙酰胆碱 (ACh) 共孵育而受到抑制。众所周知，ACh/M2 通路可以抵消肌细胞水平的 b 信号传导。事实上，百日咳毒素敏感的 Gi/o 蛋白与 M2 受体结合，可以对抗由 b 激动作用引起的 Gs 蛋白激活所触发的腺苷酸环化酶活性。体内 VNS 可能通过抑制突触前水平的交感神经驱动，显着降低左心室间质液中的 NE 浓度。迷走神经激活位于肾上腺素能神经末梢的 M2 受体，可抑制交感传出神经释放去甲肾上腺素 (NE)。 7 与 ESR 信号衰减率类似，NE 含量仅在 CHF 小鼠中显着降低，暗示“NE-to-ROS”存在因果关系。除了这些毒蕈碱机制外，VNS 诱导的心肌氧化还原变化也可能涉及一氧化氮 (NO)，因为 NO 合酶 (NOS) 抑制剂 Nv-硝基-L-精氨酸甲酯 (L-NAME) 会减弱 VNS 诱导的益处。心脏胆碱能神经元也含有 NOS，因此能够释放 NO。神经元 NO 支持 ACh 的释放，8 因此抑制 NOS 可能通过胆碱能机制间接影响 ROS。此外，NO 可以直接“淬灭”ROS 9 或抑制 NADPH 氧化酶 10，NADPH 氧化酶是实验 1 和人类 CHF 中 ROS 的主要来源。 11 在此，VSN 还减弱了 NADPH 氧化酶活性。在 CHF 中，血管紧张素 II 1 型受体在调节交感运动神经元活动的关键中继站（即延髓头端腹外侧 (RVLM) 或孤束核 (NTS)）中上调。这种上调会导致……
Reactive oxygen species (ROS) are main actors in the evolving drama of congestive heart failure (CHF), 1 a neuroendocrine disorder in which excess ROS signalling contributes to sympathetic efferent fibre hyperactivation. 2 Enhanced sympathetic outflow favours arrhythmias, myocardial remodelling/dysfunction and premature death (Figure 1), thus having pathogenetic and prognostic meaning. However, the sympathetic ‘arm’of the autonomic nervous system (ANS) acts not only as a ‘victim’of ROS but also as an ‘executioner’of further ROS-induced myocardial damage. Indeed, spill-over of catecholamines and other hypertrophic agents such as serotonin, angiotensin II, and endothelin-1 may amplify oxidative stress via their own enhanced catabolism and/or ROS-induced ROS release from mitochondria, triggering apoptosis and cell death. Yet, many unknowns still surround the ANS–ROS ‘bi-univocal’relationship in CHF. One is the role of the parasympathetic (vagal) component. Vagal nerve stimulation (VNS) limits the frequency of lethal ventricular arrhythmias in dogs, 3 and in rats it attenuates cardiac remodelling and improves survival. 4 The mechanisms for the latter, however, remain elusive. In the current issue of Cardiovascular Research, Tsutsumi et al. 5 show that VNS normalizes the in vivo rate of electron spin resonance (ESR) signal decay in infarcted mice with CHF. This shift is proportional to hydroxyl radical († OH) generation, which is typically altered in CHF models. 6 Antioxidants such as Tiron or dimethylthiourea (superoxide and† OH scavengers, respectively) mimicked the protective effect of VNS, further supporting the concept that VNS attenuates ROS production. This effect was inhibited by atropine sulphate, suggesting M2 muscarinic receptor involvement. But how did VNS-M2 drive abate excess ROS generation in these failing hearts? Here, the authors documented pre-and postjunctional cholinergic actions to suppress the ‘norepineprine (NE)–ROS axis’. In isolated cardiomyocytes, b-receptor-mediated ROS production was suppressed by co-incubation with acetylcholine (ACh). It is known that the ACh/M2 pathway can offset b-signalling at the myocyte level. Indeed, pertussis toxin-sensitive Gi/o protein coupled with M2 receptors counters adenylyl cyclase activity that is triggered by Gs protein activation due to b-agonism. In vivo VNS significantly reduced NE concentration in left ventricular interstitial fluid, likely through inhibition of sympathetic drive at the presynaptic level. Vagal activation of M2-receptors located at adrenergic nerve terminals is known to suppress norepinephrine (NE) release from sympathetic efferents. 7 In analogy to ESR signal decay rate, NE content was reduced significantly only in CHF mice, hinting to a cause–effect ‘NE-to-ROS’relationship. In addition to these muscarinic mechanisms, VNS-induced myocardial redox changes might also involve nitric oxide (NO) since the NO synthase (NOS) inhibitor Nv-nitro-L-arginine methyl ester (L-NAME) attenuated VNS-induced benefits. Cardiac cholinergic neurons also contain NOS and are therefore capable of releasing NO. Neuronal NO supports the release of ACh, 8 so inhibition of NOS might affect ROS indirectly through a cholinergic mechanism. Further, NO can ‘quench’ROS directly9 or may inhibit NADPH oxidase, 10 a major source of ROS in experimental1 and human CHF. 11 Here, VSN also attenuated NADPH oxidase activity. In CHF, angiotensin II type 1 receptors are up-regulated in critical relay stations that modulate sympathetic motor neuron activity, ie the rostral ventrolateral medulla (RVLM) or the nucleus tractus solitarius (NTS). This up-regulation leads to a …