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

MitoSNO 选择性 S-亚硝化线粒体复合物 I 作为心脏缺血再灌注损伤的新疗法

• 批准号: MC_EX_MR/M015769/1
• 负责人: Michael Murphy
• 金额: $ 100.71万
• 依托单位: MRC Centre Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_EX_MR%2FM015769%2F1
• 关键词: Selective; nitrosation; mitochondrial; complex; MitoSNO

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.

缺血再灌注 (IR) 损伤是许多临床重要病症的基础，例如心脏病发作和中风。当器官的血液供应被中断（例如由于血栓）时，就会发生缺血。如果血液供应恢复，组织就可以恢复。然而，用含氧血液对缺血器官进行再灌注会导致广泛的组织损伤，从而使患者的长期预后恶化。这种损伤主要是由再灌注过程中线粒体产生破坏性自由基引起的，导致细胞死亡。我们开发了一种名为 MitoSNO 的新型线粒体靶向药物，可防止 IR 损伤期间线粒体产生自由基。 MitoSNO 包含一种亲脂性阳离子，在缺血器官再灌注期间静脉注射后，立即驱动其快速、广泛地被心脏内的线粒体吸收。在线粒体内，MitoSNO 选择性地将一氧化氮部分转移到呼吸复合物 I 上的特定半胱氨酸上，从而防止再灌注期间通常发生的线粒体自由基产生。 5-10 分钟后，这种修饰会逆转，使线粒体恢复完全活性。啮齿动物研究表明，MitoSNO 可在临床相关的体内模型中预防心脏 IR 损伤，从而大大增强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时的器官来阻止线粒体自由基的产生。在这项研究中，我们将评估 MitoSNO 是否也能预防猪的 IR 损伤，为首次人体 I 期研究做准备。由于在心脏病发作和器官移植等其他情况下也发现了类似的 IR 损伤，MitoSNO 也可能被证明是对一系列适应症的有效治疗方法。

项目成果

Mitochondrial thiol modification by a targeted electrophile inhibits metabolism in breast adenocarcinoma cells by inhibiting enzyme activity and protein levels.

• DOI: 10.1016/j.redox.2016.01.002
• 发表时间: 2016-08
• 期刊: Redox biology
• 影响因子: 11.4
• 作者: Smith MR;Vayalil PK;Zhou F;Benavides GA;Beggs RR;Golzarian H;Nijampatnam B;Oliver PG;Smith RA;Murphy MP;Velu SE;Landar A
• 通讯作者: Landar A

Acute regional changes in myocardial strain may predict ventricular remodelling after myocardial infarction in a large animal model.

• DOI: 10.1038/s41598-021-97834-y
• 发表时间: 2021-09-15
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Mansell DS;Bruno VD;Sammut E;Chiribiri A;Johnson T;Khaliulin I;Lopez DB;Gill HS;Fraser KH;Murphy M;Krieg T;Suleiman MS;George S;Ascione R;Cookson AN
• 通讯作者: Cookson AN