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.
Highlights
Diabetic complications are responsible for the majority of expenses associated with diabetes treatment and the costs of diabetes that currently accounts for 10% of total healthcare costs, is projected to increase to 17% of health resource expenditure overD
Hyperglycemia-induced mitochondrial superoxide generation is an upstream player in the development of endothelial dysfunction and it is responsible for the activation of other sources of oxidants in the cells [8]
We compared the efficacy of AP39 and AP123, a newer mitochondrial H2S donor, against glucose-induced endothelial dysfunction and we found that mitochondrial slow-release H2S donors are >1000-fold more potent than Na2S against hyperglycemia-induced oxidant production and have beneficial effect on cellular bioenergetics in endothelial cells
Summary
Blockage of mitochondrial superoxide generation by the above methods or neutralisation by manganese superoxide dismutase (MnSOD) inhibits other sources of oxidants in endothelial cells: the activation of protein kinase C (PKC) and the polyol pathway, the formation of advanced glycation end product (AGE) and the hexosamine pathway [8]. We found that mitochondrial superoxide scavenging using paroxetine [10] or induction of uncoupling protein-2 (UCP-2) blocked the glucose-induced oxidant production in endothelial cells [11]. While these methods all reduce the mitochondrial ROS production and the associated cellular damage, neither ROS scavenging nor mitochondrial uncoupling fully restore the mitochondrial energy production. If electrons are used for superoxide generation and the protons are released through uncoupling proteins, there will be a drop in ATP production via oxidative phosphorylation
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