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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.

SUBMITTER: Gero D

PROVIDER: S-EPMC5113977 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Reductions in hydrogen sulfide (H2S) production have been implicated in the pathogenesis of vascular dysfunction in animal models of hypertension; however, no studies have examined a functional role for H2S in contributing to microvascular dysfunction in hypertensive (HTN) adults. We hypothesized that endogenous production of H2S would be reduced, impaired endothelium-dependent vasodilation would be mediated by reductions in H2S-dependent vasodilation, and vascular responsiveness to exogenous H2S (sodium sulfide) would be attenuated in HTN compared to normotensive adults. Fifteen normotensive (51±2 years; blood pressure, 116±3/76±3 mm Hg) and 14 HTN adults (57±2 years; blood pressure 140±3/89±2 mm Hg) participated. H2S biosynthetic enzyme expression (Western blot) and substrate-dependent H2S production (amperometric probe) were measured in cutaneous tissue homogenates. Red cell flux (laser Doppler flowmetry) was measured during graded perfusions of acetylcholine (ACh; 10-6-10-1 mol/L) and sodium sulfide (10-5-101 mol/L) using intradermal microdialysis; the functional role of H2S was determined using pharmacological inhibition with aminooxyacetic acid (0.5 mmol/L). H2S biosynthetic enzyme expression and substrate-dependent H2S production were reduced in HTN adults (all P<0.05). ACh-induced endothelium-dependent vasodilation was blunted in HTN adults (P=0.012). Aminooxyacetic acid attenuated ACh-induced vasodilation in normotensive adults (ACh, 1.31±0.13 versus ACh+aminooxyacetic acid, 1.07±0.09 flux/mm Hg; P=0.025) but had no effect on vasodilation in HTN adults (ACh, 1.16±0.10 versus ACh+aminooxyacetic acid, 1.37±0.11 flux/mm Hg; P=0.47). Sodium sulfide-induced vasodilation was not different between groups. Collectively, these findings indicate that while the microvasculature maintains the ability to vasodilate in response to exogenous H2S, reductions in endogenous synthesis and H2S-dependent vasodilation contribute to endothelial dysfunction in human hypertension.

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The novel mitochondria-targeted hydrogen sulfide (H₂S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro.

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Dataset Information

The novel mitochondria-targeted hydrogen sulfide (H2S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

The novel mitochondria-targeted hydrogen sulfide (H₂S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro.