Biochemical signaling by remote ischemic conditioning of the arm versus thigh: Is one raise of the cuff enough?

Cameron Dezfulian; Maia Taft; Catherine Corey; Gabrielle Hill; Nicholas Krehel; Jon C. Rittenberger; Frank X. Guyette; Sruti Shiva

摘要

Remote Ischemic Conditioning (RIC), induced by brief cycles of ischemia and reperfusion, protects vital organs from a prolonged ischemic insult. While several biochemical mediators have been implicated in RIC's mechanism of action, it remains unclear whether the localization or “dose” of RIC affects the extent of protective signaling. In this randomized crossover study of healthy individuals, we tested whether the number of cycles of RIC and its localization (arm versus thigh) determines biochemical signaling and cytoprotection. Subjects received either arm or thigh RIC and then were crossed over to receive RIC in the other extremity. Blood flow, tissue perfusion, concentrations of the circulating protective mediator nitrite, and platelet mitochondrial function were measured after each RIC cycle. We found that plasma nitrite concentration peaked after the first RIC cycle and remained elevated throughout RIC. This plasma nitrite conferred cytoprotection in an in vitro myocyte model of hypoxia/reoxygenation. Notably, though plasma nitrite returned to baseline at 24?h, RIC conditioned plasma still mediated protection. Additionally, no difference in endpoints between RIC in thigh versus arm was found. These data demonstrate that localization and “dose” of RIC does not affect cytoprotection and further elucidate the mechanisms by which nitrite contributes to RIC-dependent protection. prs.rt("abs_end"); 1. Introduction Remote ischemic conditioning (RIC) refers to brief sub-lethal ischemia applied to an area remote from the organ being targeted for protection from a future (preconditioning) or past (postconditioning) ischemic insult. In practical terms this is usually achieved in human subjects using a blood pressure cuff placed on an extremity and inflated above systolic blood pressure (often 200?mm Hg), rendering the extremity ischemic for a period of 5?min prior to deflation (which permits reperfusion) [1] ; [2] . RIC was first shown to be cardioprotective in 1993 [3] and subsequent studies have confirmed that other organs such as brain [4] ; [5] and liver [6] can be similarly protected. RIC is attractive from a clinical perspective as it is minimally invasive compared to traditional ischemic preconditioning, which involves targeting sublethal ischemia to the organ intended for protection, and carries minimal risk and discomfort [7] . While RIC has shown promise in preliminary clinical studies with surrogate endpoints [1] ; [2] ; [8] and possible survival benefits [9] ; [10] , other recent large randomized clinical trials have yielded disappointing neutral results [11] ; [12] ; [13] ; [14] . The inconsistences in the benefit of RIC between trials may derive from a lack of understanding of how best to “dose” RIC. The commonly used protocol of 5?min inflation-deflation of a blood pressure cuff placed on an upper extremity repeated for 3–4 cycles has been adopted in clinical studies [11] ; [12] ; [13] ; [14] without formal testing of the optimal dose or location in humans. Thus, it is unknown whether some or all patients would benefit from more or less than 3–4 cycles of RIC. Further, it remains unknown whether RIC applied to an upper (arm) versus lower (thigh) extremity would alter the required dose or efficacy of RIC due to considerable differences in vascular and soft tissue mass in the arm versus leg. One reason for the absence of a human dose titration of RIC is likely due to the lack of understanding of the precise mechanisms that underlie RIC-mediated protection [15] ; [16] ; [17] . Though a number of mechanisms have been proposed including neural and autonomic signaling [18] ; [19] , studies demonstrating that organ protection can be transferred from a RIC-treated animal to an untreated animal by the simple transfer of blood suggest that humoral factors are likely imperative to protection [20] ; [21] . In this regard, Rassaf and colleagues recently demonstrated that nitrite, the one electron oxidation product of nitric oxide (NO), was significantly increased in the blood after RIC and necessary and sufficient to confer cardioprotection when applied to an ex vivo heart model of ischemia/reperfusion [20] . This production of nitrite was dependent on the reactive hyperemia (RH) that ensues during the reperfusion phase of RIC and due to oxidation of nitric oxide derived from vascular endothelial nitric oxide synthase [20] . Notably, prior studies have shown that nitrite mimics the effects of RIC and mediates cytoprotection in a number of ischemia/reperfusion models, and this is due to its inhibitory effect on mitochondrial respiration in the target organ [20] ; [22] ; [23] ; [24] ; [25] . Thus, the extent of RH and the resulting concentration of plasma nitrite generated represent a quantifiable parameter to measure the “dose” of RIC. Here we measure RH and plasma nitrite as physiological and biochemical signaling mediators of RIC and use these parameters to quantify the “dose” of RIC delivered using sequentia

机译：短暂的缺血和再灌注循环可诱发远程缺血性调节（RIC），可保护重要器官免受长时间的缺血性损伤。尽管有几种生化介质与RIC的作用机制有关，但尚不清楚RIC的定位或“剂量”是否会影响保护性信号传导的程度。在这项针对健康个体的随机交叉研究中，我们测试了RIC的循环数及其定位（臂对大腿）是否决定了生化信号传导和细胞保护作用。受试者接受手臂或大腿RIC，然后越过另一端接受RIC。在每个RIC周期后，测量血流量，组织灌注，循环中的保护性亚硝酸盐浓度和血小板线粒体功能。我们发现血浆亚硝酸盐浓度在第一个RIC循环后达到峰值，并在整个RIC内保持升高。这种血浆亚硝酸盐在缺氧/复氧的体外心肌细胞模型中赋予了细胞保护作用。值得注意的是，尽管血浆亚硝酸盐在24小时后恢复到基线，但RIC条件血浆仍能介导保护作用。另外，在大腿与手臂之间的RIC之间没有发现终点差异。这些数据表明，RIC的定位和“剂量”不影响细胞保护，并进一步阐明了亚硝酸盐有助于RIC依赖性保护的机制。 prs.rt（“ abs_end”）; 1.引言远程缺血性调节（RIC）是指短暂的亚致死性缺血，适用于远离目标器官的区域，以保护其免受将来（预处理）或过去（后处理）缺血性损伤的侵害。实际上，这通常是通过将血压袖套置于四肢并膨胀至高于收缩压（通常为200？mm Hg）而在人类受试者中实现的，从而使四肢缺血后放气5分钟（允许放气）。再灌注）[1]; [2]。 RIC在1993年首次被证明具有心脏保护作用[3]，随后的研究证实了其他器官，例如大脑[4]; [5]和肝脏[6]可以得到类似的保护。从临床角度来看，RIC具有吸引力，因为与传统的缺血预处理相比，RIC具有微创性，后者涉及将致死性局部缺血靶向要保护的器官，并具有最小的风险和不适感[7]。尽管RIC在具有替代终点的初步临床研究中显示出了希望[1]; [2]; [8]和可能的生存利益[9]; [10]，其他最近的大型随机临床试验也产生令人失望的中性结果[11]; [12]; [13]; [14]。两次试验之间RIC获益的不一致可能是由于缺乏对如何最佳“剂量” RIC的理解。临床研究中采用了通常的方法，即将放置在上肢的血压袖带进行5？min充气-放气，重复3–4个循环[11]。 [12]; [13]; [14]没有对人体的最佳剂量或位置进行正式测试。因此，尚不清楚部分或全部患者是否将从RIC的少于或少于3至4个周期中受益。此外，由于手臂和腿部的血管和软组织的质量存在很大差异，将RIC应用于上肢（手臂）还是下肢（大腿）是否会改变RIC所需的剂量或功效仍是未知的。缺乏人为剂量滴定RIC的一个原因很可能是由于对RIC介导的保护机制的确切机制缺乏了解[15]; [16]; [17]。尽管已经提出了许多机制，包括神经信号和自主信号[18]。 [19]，研究表明可以通过简单的血液转移将器官保护从RIC处理的动物转移到未经处理的动物，这表明体液因素可能对保护至关重要。[20] [21]。在这方面，Rassaf及其同事最近证明，RIC后，血液中一氧化氮（NO）的一种电子氧化产物亚硝酸盐显着增加，并且在应用于体外缺血性心脏模型/再灌注[20]。亚硝酸盐的产生取决于RIC再灌注阶段发生的反应性充血（RH），并且归因于源自血管内皮一氧化氮合酶的一氧化氮的氧化[20]。值得注意的是，先前的研究表明，亚硝酸盐在许多缺血/再灌注模型中模仿RIC的作用并介导细胞保护作用，这是由于其对靶器官线粒体呼吸的抑制作用[20]; [22]; [23]; [24]; [25]。因此，RH的程度和所产生的血浆亚硝酸盐的浓度代表了可测量的RIC剂量参数。在这里，我们将RH和血浆亚硝酸盐作为RIC的生理和生化信号传导介质进行测量，并使用这些参数来量化使用偶发性疾病而产生的RIC的“剂量”

Biochemical signaling by remote ischemic conditioning of the arm versus thigh: Is one raise of the cuff enough?

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