title: 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.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Gabor
authors.initials: G
authors.lastname: Olah
authors.forename: Katalin
authors.initials: K
authors.lastname: Modis
authors.forename: Ciro
authors.initials: C
authors.lastname: Coletta
authors.forename: Gabriella
authors.initials: G
authors.lastname: Kulp
authors.forename: Domokos
authors.initials: D
authors.lastname: Gerö
authors.forename: Petra
authors.initials: P
authors.lastname: Szoleczky
authors.forename: Tuanjie
authors.initials: T
authors.lastname: Chang
authors.forename: Zongmin
authors.initials: Z
authors.lastname: Zhou
authors.forename: Lingyun
authors.initials: L
authors.lastname: Wu
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
mesh_terms: D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental; D042783:Endothelial Cells; D004730:Endothelium, Vascular / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology; D006706:Homeostasis; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D006943:Hyperglycemia / Q000188:drug therapy* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D020011:Protective Agents / Q000627:therapeutic use; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D020011:Protective Agents; D017382:Reactive Oxygen Species; D005947:Glucose; D006862:Hydrogen Sulfide