Bolli R, Dawn B, Tang X L, Qiu Y, Ping P, Xuan Y T, Jones W K, Takano H, Guo Y, Zhang J
Basic Res Cardiol. 1998 Oct;93(5):325-38. doi: 10.1007/s003950050101.
Ischemic preconditioning (PC) occurs in two phases: an early phase, which lasts 2-3 h, and a late phase, which begins 12-24 h later and lasts 3-4 days. The mechanism for the late phase of PC has been the focus of intense investigation. We have recently proposed the "NO hypothesis of late PC", which postulates that NO plays a prominent role both in initiating and in mediating this cardioprotective response. The purpose of this essay is to review the evidence supporting the NO hypothesis of late PC and to discuss its implications. We propose that, on day 1, a brief ischemic stress causes increased production of NO (probably via eNOS) and .O2-, which then react to form ONOO-, ONOO-, in turn, activates the epsilon isoform of protein kinase C (PKC), either directly or via its reactive byproducts such as .OH. Both NO and secondary species derived from .O2- could also stimulate PKC epsilon independently. PKC epsilon activation triggers a complex signaling cascade that involves tyrosine kinases (among which Src and Lck appear to be involved) and probably other kinases, the transcription factor NF-kappa B, and most likely other as yet unknown components, resulting in increased transcription of the iNOS gene and increased iNOS activity on day 2, which is responsible for the protection during the second ischemic challenge. Tyrosine kinases also appear to be involved on day 2, possibly by modulating iNOS activity. According to this paradigm, NO plays two completely different roles in late PC: on day 1, it initiates the development of this response, whereas on day 2, it protects against myocardial ischemia. We propose that two different NOS isoforms are sequentially involved in late PC, with eNOS generating the NO that initiates the development of the PC response on day 1 and iNOS then generating the NO that protects against recurrent ischemia on day 2. The NO hypothesis of late PC puts forth a comprehensive paradigm that can explain both the initiation and the mediation of this complex phenomenon. Besides its pathophysiological implications, this hypothesis has potential clinical reverberations, since NO donors (i.e., nitrates) are widely used clinically and could be used to protect the ischemic myocardium in patients.
缺血预处理（PC）分为两个阶段：早期阶段持续2 - 3小时，晚期阶段在12 - 24小时后开始，持续3 - 4天。PC晚期阶段的机制一直是深入研究的重点。我们最近提出了“晚期PC的NO假说”，该假说假定NO在启动和介导这种心脏保护反应中都起着重要作用。本文的目的是综述支持晚期PC的NO假说的证据并讨论其意义。我们提出，在第1天，短暂的缺血应激会导致NO（可能通过内皮型一氧化氮合酶（eNOS））和超氧阴离子（.O2-）生成增加，它们随后反应形成过氧亚硝酸根（ONOO-），ONOO-进而直接或通过其反应性副产物如羟自由基（.OH）激活蛋白激酶C（PKC）的ε亚型。来自.O2-的NO和次级产物也可独立刺激PKCε。PKCε激活触发一个复杂的信号级联反应，涉及酪氨酸激酶（其中Src和Lck似乎参与其中）以及可能的其他激酶、转录因子核因子κB（NF-κB），很可能还有其他尚未知晓的成分，导致第2天诱导型一氧化氮合酶（iNOS）基因转录增加和iNOS活性增强，这负责在第二次缺血挑战期间提供保护。酪氨酸激酶在第2天似乎也有参与，可能是通过调节iNOS活性。根据这一模式，NO在晚期PC中发挥两种完全不同的作用：在第1天，它启动这种反应的发展，而在第2天，它保护心肌免受缺血损伤。我们提出两种不同的一氧化氮合酶（NOS）亚型依次参与晚期PC，eNOS在第1天生成启动PC反应发展的NO，然后iNOS在第2天生成保护心肌免受反复缺血损伤的NO。晚期PC的NO假说提出了一个全面的模式，能够解释这一复杂现象的启动和介导过程。除了其病理生理学意义外，这一假说还具有潜在的临床影响，因为NO供体（即硝酸盐）在临床上广泛使用，可用于保护患者的缺血心肌。
