Selective S-nitrosation of mitochondrial complex I by MitoSNO as a new therapy for cardiac ischaemia-reperfusion injury

缺血再灌注（IR）损伤是许多临床重要疾病的基础，如心脏病发作和中风。当器官的血液供应中断时，例如由于血凝块，就会发生缺血。如果血液供应恢复，组织就能恢复。然而，缺血器官再灌注含氧血液会导致广泛的组织损伤，从而恶化患者的长期预后。这种损伤主要是由线粒体在再灌注过程中产生的破坏性自由基引起的，从而导致细胞死亡。我们已经开发出一种新的线粒体靶向药物，称为MitoSNO，可以防止线粒体在IR损伤期间产生自由基。在缺血器官再灌注期间静脉注射MitoSNO后，MitoSNO包含亲脂性阳离子，促使其迅速广泛地摄取到心脏内的线粒体。在线粒体内，MitoSNO选择性地将一氧化氮片段转移到呼吸复合体I上的特定半胱氨酸上，从而阻止再灌注过程中正常发生的线粒体自由基产生。这种修饰在5-10分钟后被逆转，使线粒体恢复完全活性。啮齿类动物研究表明，在临床相关的体内模型中，MitoSNO可以预防心脏IR损伤，从而大大促进心脏功能的长期恢复。MitoSNO是独一无二的，因为没有其他保护性疗法可以应用于再灌注器官来阻止线粒体自由基的产生。在这项研究中，MitoSNO将被评估，看看它是否也对猪的IR损伤有保护作用，为第一阶段的人体研究做准备。由于在其他情况下也发现类似的IR损伤，例如心脏病发作和器官移植，MitoSNO也可能被证明是一种有用的治疗方法。

Ischaemia-reperfusion (IR) injury underlies many clinically important conditions, such as heart attack and stroke. Ischaemia occurs when the blood supply to an organ is interrupted, for example by a blood clot. If the blood supply is restored the tissue can recover. However, reperfusion of the ischaemic organ with oxygenated blood leads to extensive tissue damage that worsens the long-term prognosis for the patient. This injury is initiated largely by the production of damaging free radicals from mitochondria during reperfusion that leads to cell death. We have developed a novel mitochondria-targeted drug called MitoSNO that prevents free radical production from mitochondria during IR injury. MitoSNO comprises a lipophilic cation that drives its rapid and extensive uptake into mitochondria within the heart immediately following its intravenous injection during reperfusion of the ischaemic organ. Within mitochondria MitoSNO selectively transfers a nitric oxide moiety onto a particular cysteine on respiratory complex I, thereby preventing the mitochondrial free radical production that normally occurs during reperfusion. This modification is reversed after 5-10 mins allowing the mitochondria to return to full activity. Rodent studies have shown that MitoSNO prevents cardiac IR injury in clinically relevant in vivo models, thereby greatly enhancing the long-term recovery of heart function. MitoSNO is unique as no other protective therapies can be applied to organs at reperfusion to block mitochondrial free radical production. In this study MitoSNO will be assessed to see if it is also protective against IR injury in pigs in preparation for a first-in-man Phase I study. As similar IR injury is found in other situations, such as heart attack and organ transplantation, MitoSNO may also prove a useful therapeutic for a range of indications.