Do mitochondria-targeted hydrogen sulfide (H2S) donors prevent and / or reverse diabetic endothelial dysfunction?

线粒体靶向的硫化氢 (H2S) 供体是否可以预防和/或逆转糖尿病内皮功能障碍？

• 批准号: MR/M022706/1
• 负责人: Matthew Whiteman
• 金额: $ 46.71万
• 依托单位: UNIVERSITY OF EXETER
• 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=MR%2FM022706%2F1
• 关键词: Do; mitochondria; targeted; hydrogen; sulfide

Diabetes has a significant personal impact on the sufferer since it is often associated with life-changing complications to blood vessels. One of the most feared complications is cardiovascular disease such as high blood pressure, or blocked arteries (atherosclerosis). This not only severely affects the quality of life of the sufferer and their family, but also impacts on wider society through the financial burden of both healthcare and benefits. More than 3.2 million people in the UK have diabetes and this number is expected to double by 2035. A further 630,000 people are unaware they have this disease. Treating this diabetes costs the NHS £14 billion per year (10% of the NHS budget) and of this, 79% is needed to treat the diabetic complications alone. At present there are no drugs for treating diabetic complications and there is a great interest in finding drugs for this purpose. One of the first steps in the development of diabetic complications is damage to the cells which form a protective layer around the blood vessels (the endothelial cells or EC). These cells sit on top of the muscles which control whether a blood vessel tightens (constricts) or relaxes. In diabetes too much blood sugar (hyperglycaemia) causes mitochondria, a tiny but vital component the EC (and all cells) which controls energy metabolism, to stop working. Instead of using oxygen to efficiently convert sugar into 'energy', damaged mitochondria generate toxic oxygen metabolites called 'free radicals'. As a result, EC do not respond to normal body signals which tell the blood vessel to relax. Instead, they respond better to body signals which tell the blood vessels to constrict. This results in high blood pressure. In addition, the damage caused attracts inflammatory cells, which accumulate, and stick to the damaged part of the blood vessel. Eventually the blood vessel becomes so 'clogged up' that it severely restricts, and can stop, blood flowing through the vessel. When this happens in the blood vessels around the heart it can cause a heart attack (and death) and if this happens in the blood vessels of the eye, it can cause blindness. We have previously found that blood levels of the gas hydrogen sulfide (H2S) area lot lower in people with diabetes than in healthy people. We, and others, have also seen this in several animal models of diabetes. H2S is made in very small amounts by the EC lining blood vessels and it helps the blood vessels to relax. Lower blood H2S levels in people (and animals) with diabetes are linked to higher blood pressure, poorer circulation and poorer control of blood sugar and insulin. H2S also protects mitochondria from the damaging effects of hyperglycaemia and the effects of toxic products (e.g. 'free radicals') that are formed in the blood during hyperglycaemia. Removing H2S damages blood vessels and worsens the damage to mitochondria, EC and blood vessels. To restore the H2S that is lost during diabetes we have developed a brand new class of potential drug molecules which make very low amounts of H2S and deliver the H2S to mitochondria where it appears to be most needed. We have called these new molecules, which we have patented, 'mitochondria-targeted H2S donors' (mtH2SD). Our preliminary studies have shown that very low doses of these molecules can protect mitochondria in EC from the detrimental effects of hyperglycaemia and dilate blood vessels.This study will firstly investigate how mtH2SD protect isolated EC from hyperglycaemia and then examine whether they can reverse hyperglycaemia-induced damage to these cells using blood vessels obtained from control and diabetic animals treated with the mtH2SD. Our team has extensive experience in H2S biology and our combined experience will ensure that this project provides reliable results that will inform clinicians, the pharmaceutical industry, scientists and most importantly patients on the therapeutic potential of mtH2SD in treating diabetic complications.

糖尿病对患者有重大的个人影响，因为它通常与改变生活的血管并发症有关。最令人恐惧的并发症之一是心血管疾病，如高血压或动脉阻塞（动脉粥样硬化）。这不仅严重影响了患者及其家庭的生活质量，而且通过医疗保健和福利的经济负担影响了更广泛的社会。英国有超过320万人患有糖尿病，预计到2035年这一数字将翻一番。另有63万人不知道他们患有这种疾病。治疗这种糖尿病每年花费NHS 140亿英镑（NHS预算的10%），其中79%需要单独治疗糖尿病并发症。目前还没有治疗糖尿病并发症的药物，人们对寻找用于此目的的药物有很大的兴趣。 糖尿病并发症发展的第一步之一是对在血管周围形成保护层的细胞（内皮细胞或EC）的损伤。这些细胞位于肌肉的顶部，控制血管是收紧（收缩）还是放松。在糖尿病中，过多的血糖（高血糖症）会导致线粒体，一个微小但重要的组成部分，EC（和所有细胞）控制能量代谢，停止工作。受损的线粒体不是利用氧气有效地将糖转化为“能量”，而是产生称为“自由基”的有毒氧代谢物。因此，EC不响应告诉血管放松的正常身体信号。相反，它们对告诉血管收缩的身体信号反应更好。这会导致高血压。此外，所造成的损害吸引炎症细胞，这些细胞积聚并粘附在血管的受损部分。最终，血管变得如此“堵塞”，以至于严重限制并阻止血液流过血管。当这种情况发生在心脏周围的血管时，它可能会导致心脏病发作（和死亡），如果这种情况发生在眼睛的血管中，它可能会导致失明。我们以前发现，糖尿病患者血液中硫化氢（H2S）的含量比健康人低得多。我们和其他人也在几种糖尿病动物模型中看到了这一点。H2S是由EC内衬血管制造的，它有助于血管放松。患有糖尿病的人（和动物）的血液H2S水平较低与血压升高，血液循环不良以及血糖和胰岛素控制不良有关。H2S还保护线粒体免受高脂血症的破坏作用和高脂血症期间在血液中形成的有毒产物（例如“自由基”）的影响。清除H2S损伤血管，减轻线粒体、EC和血管的损伤。为了恢复糖尿病期间丢失的H2S，我们开发了一类全新的潜在药物分子，它们产生非常少量的H2S，并将H2S输送到线粒体中最需要的地方。我们将这些新分子命名为“靶向H2S供体”（mtH2SD）。我们的初步研究表明，很低剂量的这些分子可以保护EC中的线粒体免受高血糖的不利影响，并扩张血管。本研究将首先研究mtH2SD如何保护分离的EC免受高血糖的影响，然后使用来自对照和糖尿病动物的血管检测它们是否可以逆转高血糖对这些细胞的损伤。我们的团队在H2S生物学方面拥有丰富的经验，我们的综合经验将确保该项目提供可靠的结果，将告知临床医生，制药行业，科学家和最重要的患者mtH2SD在治疗糖尿病并发症方面的治疗潜力。

项目成果

AP39, A Mitochondrially Targeted Hydrogen Sulfide Donor, Exerts Protective Effects in Renal Epithelial Cells Subjected to Oxidative Stress in Vitro and in Acute Renal Injury in Vivo.

• DOI: 10.1097/shk.0000000000000478
• 发表时间: 2016-01
• 期刊: Shock (Augusta, Ga.)
• 作者: Ahmad A;Olah G;Szczesny B;Wood ME;Whiteman M;Szabo C
• 通讯作者: Szabo C

Hydrogen Sulfide Is a Novel Protector of the Retinal Glycocalyx and Endothelial Permeability Barrier.

• DOI: 10.3389/fcell.2021.724905
• 发表时间: 2021
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Allen CL;Wolanska K;Malhi NK;Benest AV;Wood ME;Amoaku W;Torregrossa R;Whiteman M;Bates DO;Whatmore JL
• 通讯作者: Whatmore JL

Investigating the generation of hydrogen sulphide from the phosphinodithioate slow-release donor GYY4137: Novel products and experimental tools

研究二硫代膦缓释供体 GYY4137 产生硫化氢：新产品和实验工具

• DOI: 10.1016/j.niox.2015.02.126
• 发表时间: 2015
• 期刊: Nitric Oxide
• 作者: Alexander B

Hydrogen Sulfide and Polysulfides Mimic the Effects of Hypoxia in Bovine Pulmonary and Porcine Coronary Arteries

硫化氢和多硫化物模拟牛肺动脉和猪冠状动脉缺氧的影响

• 发表时间: 2017
• 期刊: FASEB JOURNAL
• 影响因子: 4.8
• 作者: Forgan Leonard George