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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.
Pharmacol Res 2016; 113(Pt A):186-198PR

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+Show Affiliations

University of Exeter Medical School, Exeter, UK. Electronic address: gerodomokos@yahoo.com.University of Exeter Medical School, Exeter, UK; Biosciences, College of Life and Environmental Sciences, University of Exeter, UK.Biosciences, College of Life and Environmental Sciences, University of Exeter, UK.University of Exeter Medical School, Exeter, UK.IRSET-UMR INSERM U1085, Equipe 3-Stress, Membrane et Signalisation, Rennes Cedex, France.University of Exeter Medical School, Exeter, UK.Biosciences, College of Life and Environmental Sciences, University of Exeter, UK.University of Exeter Medical School, Exeter, UK. Electronic address: m.whiteman@exeter.ac.uk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27565382

Citation

Gerő, Domokos, et al. "The Novel Mitochondria-targeted Hydrogen Sulfide (H2S) Donors AP123 and AP39 Protect Against Hyperglycemic Injury in Microvascular Endothelial Cells in Vitro." Pharmacological Research, vol. 113, no. Pt A, 2016, pp. 186-198.
Gerő D, Torregrossa R, Perry A, et al. The novel mitochondria-targeted hydrogen sulfide (H2S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro. Pharmacol Res. 2016;113(Pt A):186-198.
Gerő, D., Torregrossa, R., Perry, A., Waters, A., Le-Trionnaire, S., Whatmore, J. L., ... Whiteman, M. (2016). The novel mitochondria-targeted hydrogen sulfide (H2S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro. Pharmacological Research, 113(Pt A), pp. 186-198. doi:10.1016/j.phrs.2016.08.019.
Gerő D, et al. The Novel Mitochondria-targeted Hydrogen Sulfide (H2S) Donors AP123 and AP39 Protect Against Hyperglycemic Injury in Microvascular Endothelial Cells in Vitro. Pharmacol Res. 2016;113(Pt A):186-198. PubMed PMID: 27565382.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The novel mitochondria-targeted hydrogen sulfide (H2S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro. AU - Gerő,Domokos, AU - Torregrossa,Roberta, AU - Perry,Alexis, AU - Waters,Alicia, AU - Le-Trionnaire,Sophie, AU - Whatmore,Jacqueline L, AU - Wood,Mark, AU - Whiteman,Matthew, Y1 - 2016/08/23/ PY - 2016/06/30/received PY - 2016/08/10/revised PY - 2016/08/14/accepted PY - 2016/10/21/pubmed PY - 2017/12/21/medline PY - 2016/8/28/entrez KW - Bioenergetics KW - Complex II KW - Electron transport KW - Endothelial cells KW - Hydrogen sulfide KW - Hyperglycemia KW - Oxidative stress KW - SQR KW - Superoxide SP - 186 EP - 198 JF - Pharmacological research JO - Pharmacol. Res. VL - 113 IS - Pt A N2 - 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. SN - 1096-1186 UR - https://www.unboundmedicine.com/medline/citation/27565382/The_novel_mitochondria_targeted_hydrogen_sulfide__H2S__donors_AP123_and_AP39_protect_against_hyperglycemic_injury_in_microvascular_endothelial_cells_in_vitro_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1043-6618(16)30631-4 DB - PRIME DP - Unbound Medicine ER -