Hydrogen sulfide replacement therapy protects the vascular endothelium in hyperglycemia by preserving mitochondrial function.

Abstract

The goal of the present studies was to investigate the role of changes in hydrogen sulfide (H(2)S) homeostasis in the pathogenesis of hyperglycemic endothelial dysfunction. Exposure of bEnd3 microvascular endothelial cells to elevated extracellular glucose (in vitro "hyperglycemia") induced the mitochondrial formation of reactive oxygen species (ROS), which resulted in an increased consumption of endogenous and exogenous H(2)S. Replacement of H(2)S or overexpression of the H(2)S-producing enzyme cystathionine-γ-lyase (CSE) attenuated the hyperglycemia-induced enhancement of ROS formation, attenuated nuclear DNA injury, reduced the activation of the nuclear enzyme poly(ADP-ribose) polymerase, and improved cellular viability. In vitro hyperglycemia resulted in a switch from oxidative phosphorylation to glycolysis, an effect that was partially corrected by H(2)S supplementation. Exposure of isolated vascular rings to high glucose in vitro induced an impairment of endothelium-dependent relaxations, which was prevented by CSE overexpression or H(2)S supplementation. siRNA silencing of CSE exacerbated ROS production in hyperglycemic endothelial cells. Vascular rings from CSE(-/-) mice exhibited an accelerated impairment of endothelium-dependent relaxations in response to in vitro hyperglycemia, compared with wild-type controls. Streptozotocin-induced diabetes in rats resulted in a decrease in the circulating level of H(2)S; replacement of H(2)S protected from the development of endothelial dysfunction ex vivo. In conclusion, endogenously produced H(2)S protects against the development of hyperglycemia-induced endothelial dysfunction. We hypothesize that, in hyperglycemic endothelial cells, mitochondrial ROS production and increased H(2)S catabolism form a positive feed-forward cycle. H(2)S replacement protects against these alterations, resulting in reduced ROS formation, improved endothelial metabolic state, and maintenance of normal endothelial function.

• Authors: Kunihiro Suzuki, Gabor Olah, Katalin Modis, Ciro Coletta, Gabriella Kulp, Domokos Gerö, Petra Szoleczky, Tuanjie Chang, Zongmin Zhou, Lingyun Wu, Rui Wang, Andreas Papapetropoulos, Csaba Szabo
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 33 Pg. 13829-34 (Aug 16 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21808008 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Protective Agents
• Reactive Oxygen Species
• Glucose
• Hydrogen Sulfide

Topics

• Animals
• Cell Line
• Diabetes Mellitus, Experimental
• Endothelial Cells
• Endothelium, Vascular (drug effects)
• Glucose (pharmacology)
• Homeostasis
• Hydrogen Sulfide (metabolism, pharmacology, therapeutic use)
• Hyperglycemia (drug therapy, pathology)
• Mitochondria (drug effects, metabolism)
• Protective Agents (therapeutic use)
• Rats
• Reactive Oxygen Species (metabolism)