432 - Mitochondria-Targeted Hydrogen Sulfide Donors Protect Microvascular Endothelial Cells from Hyperglycaemia-Inducted Metabolic Changes and Oxidative Damage

Abstract

There is decreased bioavailability of the gas hydrogen sulfide (H 2 S) in humans with diabetes and several animal models of this disease. The loss of H 2 S is thought to be due, at least in part, to its consumption by detrimental oxidants induced in the diabetic vasculature by periods of hyperglycaemia (HG) and results in mitochondrial and endothelial dysfunction, contributing to the development of diabetic vascular complications. Therefore, strategies which either protect or reverse HG-induced mitochondrial damage may represent a novel approach to treat diabetic angiopathies. We have previously shown that mitochondria-targeted H 2 S donor compounds such as AP39, prevented and/or reversed mitochondrial and cellular damage in in vivo models of cardiac arrest, myocardial infarction, hypertension, kidney IRI and organ transplantation leading us to propose that mitochondrial- H 2 S would also be beneficial in HG-induced endothelial toxicity. We have therefore synthesised a series of novel mitochondria-targeted hydrogen sulfide donors containing mitochondria-targeting motifs (such as triphenylphosphonium decanoate) coupled to molecules we have identified as H 2 S releasing agents (a) anethole dithiolethione (e.g. AP39), (b) thiohydroxybenzamide (e.g. AP123) as well as a novel H 2 S donor moiety (c) 5-(4-hydroxyphenyl)-3H-1,2-dithiol-3-one (e.g. RT-01). We investigated the protective effects of the compounds against HG-induced oxidative stress and metabolic changes in isolated mouse brain microvascular endothelial cells. HG induced significant increase TCA cycle activity, elevated mitochondrial membrane potential and mitochondrial oxidant production and lower mitochondrial electron transport. AP39, AP123 and RT-01 (30-300nM) decreased these detrimental metabolic changes, increased electron transport at respiratory complex III and improved the cellular metabolism. Mitochondrial targeting of H 2 S also induced >1000-fold increase in the potency of H 2 S against HG-induced injury c.f. non-targeted H 2 S. The high potency and long-lasting effect elicited by these H 2 S donors strongly suggests mitochondria-targeted H 2 S could be useful against diabetic angiopathies and other vascular disorders.