title: The novel mitochondria-targeted hydrogen sulfide (H2S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro.
abstract: The development of diabetic vascular complications is initiated, at least in part, by mitochondrial reactive oxygen species (ROS) production in endothelial cells. Hyperglycemia induces superoxide production in the mitochondria and initiates changes in the mitochondrial membrane potential that leads to mitochondrial dysfunction. Hydrogen sulfide (H2S) supplementation has been shown to reduce the mitochondrial oxidant production and shows efficacy against diabetic vascular damage in vivo. However, the half-life of H2S is very short and it is not specific for the mitochondria. We have therefore evaluated two novel mitochondria-targeted anethole dithiolethione and hydroxythiobenzamide H2S donors (AP39 and AP123 respectively) at preventing hyperglycemia-induced oxidative stress and metabolic changes in microvascular endothelial cells in vitro. Hyperglycemia (HG) induced significant increase in the activity of the citric acid cycle and led to elevated mitochondrial membrane potential. Mitochondrial oxidant production was increased and the mitochondrial electron transport decreased in hyperglycemic cells. AP39 and AP123 (30-300nM) decreased HG-induced hyperpolarisation of the mitochondrial membrane and inhibited the mitochondrial oxidant production. Both H2S donors (30-300nM) increased the electron transport at respiratory complex III and improved the cellular metabolism. Targeting H2S to mitochondria retained the cytoprotective effect of H2S against glucose-induced damage in endothelial cells suggesting that the molecular target of H2S action is within the mitochondria. Mitochondrial targeting of H2S also induced >1000-fold increase in the potency of H2S against hyperglycemia-induced injury. The high potency and long-lasting effect elicited by these H2S donors strongly suggests that these compounds could be useful against diabetic vascular complications.
authors: University of Exeter Medical School, Exeter, UK. Electronic address: gerodomokos@yahoo.com.
authors: Domokos
authors: D
authors: Gerő
authors: University of Exeter Medical School, Exeter, UK; Biosciences, College of Life and Environmental Sciences, University of Exeter, UK.
authors: Roberta
authors: R
authors: Torregrossa
authors: Biosciences, College of Life and Environmental Sciences, University of Exeter, UK.
authors: Alexis
authors: A
authors: Perry
authors: University of Exeter Medical School, Exeter, UK.
authors: Alicia
authors: A
authors: Waters
authors: IRSET-UMR INSERM U1085, Equipe 3-Stress, Membrane et Signalisation, Rennes Cedex, France.
authors: Sophie
authors: S
authors: Le-Trionnaire
authors: University of Exeter Medical School, Exeter, UK.
authors: Jacqueline L
authors: JL
authors: Whatmore
authors: Biosciences, College of Life and Environmental Sciences, University of Exeter, UK.
authors: Mark
authors: M
authors: Wood
authors: University of Exeter Medical School, Exeter, UK. Electronic address: m.whiteman@exeter.ac.uk.
authors: Matthew
authors: M
authors: Whiteman
mesh_terms: D000818:Animals; D002460:Cell Line; D003920:Diabetes Mellitus / Q000378:metabolism / Q000503:physiopathology; D004579:Electron Transport / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism*; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013871:Thiones / Q000494:pharmacology*
chemical_list: C000610725:AP39 compound; D009943:Organophosphorus Compounds; D020011:Protective Agents; D017382:Reactive Oxygen Species; D013871:Thiones; D005947:Glucose; D006862:Hydrogen Sulfide
keywords: Bioenergetics; Complex II; Electron transport; Endothelial cells; Hydrogen sulfide; Hyperglycemia; Oxidative stress; SQR; Superoxide