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

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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.