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

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。最可怕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）。这不仅严重影响患者及其家人的生活质量，而且还通过医疗保健和福利的经济负担影响到更广泛的社会。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63万人不知道自己患有这种疾病。治疗糖尿病每年要花费NHS 140亿英镑（占NHS预算的10%），其中79%需要用于治疗糖尿病并发症。目前还没有治疗糖尿病并发症的药物，因此人们对寻找治疗糖尿病的药物非常感兴趣。糖尿病并发症发生的第一步是血管周围形成保护层的细胞（内皮细胞或EC）受到损害。这些细胞位于肌肉的顶部，控制血管是收缩还是放松。糖尿病患者血糖过高（高血糖）会导致线粒体停止工作，线粒体是EC（以及所有细胞）中控制能量代谢的微小但至关重要的组成部分。受损的线粒体不是利用氧气有效地将糖转化为“能量”，而是产生有毒的氧代谢物，称为“自由基”。因此，EC对告诉血管放松的正常身体信号没有反应。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，造成的损伤会吸引炎症细胞，这些细胞会积聚并粘附在受损的血管上。最终，血管变得如此“堵塞”，它严重限制，甚至可以停止血液流经血管。当这种情况发生在心脏周围的血管中时，它会导致心脏病发作（甚至死亡），如果发生在眼睛的血管中，它会导致失明。我们之前发现，糖尿病患者血液中硫化氢气体（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是由血管内壁的EC产生的，数量非常少，它有助于血管放松。糖尿病患者（和动物）血液中H2S水平较低与高血压、血液循环较差、血糖和胰岛素控制较差有关。H2S还可以保护线粒体免受高血糖和有毒产物（如葡萄糖）的破坏作用。“自由基”)在高血糖时在血液中形成。去除H2S会损伤血管，加重对线粒体、EC和血管的损伤。为了恢复在糖尿病期间丢失的H2S，我们已经开发出一种全新的潜在药物分子，它可以产生非常少量的H2S，并将H2S输送到线粒体中，这似乎是最需要的。我们将这些已经获得专利的新分子称为“线粒体靶向H2S供体”（mtH2SD）。我们的初步研究表明，极低剂量的这些分子可以保护EC中的线粒体免受高血糖和血管扩张的有害影响。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，然后利用mtH2SD治疗的对照和糖尿病动物的血管，研究它们是否可以逆转高血糖诱导的对这些细胞的损伤。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，为临床医生、制药行业、科学家和最重要的患者提供mtH2SD在治疗糖尿病并发症方面的治疗潜力。

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.