P21: Cytoprotective effects of AP39, a mitochondrially targeted hydrogen sulfide donor in oxidatively stressed endothelial cells: Protection against the loss of cell viability and bioenergetics and attenuation of mitochondrial DNA injury

Abstract

The purpose of the current study was to investigate the effect of the recently synthesized mitochondrially-targeted hydrogen sulfide (H2S) donor, AP39, on bioenergetics, viability and mitochondrial DNA integrity of the murine microvascular endothelial cell line bEnd.3 in vitro, under normal conditions, and during oxidative stress induced by glucose oxidase. Administration of AP39 (30–300 nM) to bEnd.3 cells increased intracellular H2S levels, with preferential response seen in the mitochondrial regions. Consistently with the bioenergetic effect of authentic H2S, AP39 exerted a concentration-dependent effect on mitochondrial activity, which consisted from a stimulation of mitochondrial electron transport and cellular bioenergetic function at lower concentrations (30–100 nM), followed by an inhibitory effect at a higher concentration (300 nM). AP39 did not affect mitochondrial or nuclear DNA integrity under basal conditions. Under oxidative stress conditions induced by glucose oxidase, there was a suppression of cell viability, and an inhibition of cellular bioenergetic function. AP39 pretreatment protected the cells against these responses. In accordance with our recent studies, glucose oxidase treatment induced a preferential damage to the mitochondrial DNA and AP39 (100 nM) pretreatment protected against this loss of mitochondrial DNA integrity. In conclusion, AP39 induced antioxidant and cytoprotective effects under oxidative stress conditions, which includes a protection against the loss of mitochondrial DNA integrity. Given the recent data indicating a direct causative effect of mitochondrial DNA damage in cell death, we speculate that maintenance of mitochondrial DNA integrity may be a novel mechanisms through which H2S can exert cytoprotective effects.