title: Regulation of Vascular Tone, Angiogenesis and Cellular Bioenergetics by the 3-Mercaptopyruvate Sulfurtransferase/H2S Pathway: Functional Impairment by Hyperglycemia and Restoration by DL-α-Lipoic Acid.
abstract: Hydrogen sulfide (H2S), as a reducing agent and an antioxidant molecule, exerts protective effects against hyperglycemic stress in the vascular endothelium. The mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is an important biological source of H2S. We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may have an adverse effect on cellular homeostasis. In the current study, given the importance of H2S as a vasorelaxant, angiogenesis stimulator and cellular bioenergetic mediator, we first determined whether the 3-MST/H2S system plays a physiological regulatory role in endothelial cells. Next, we tested whether a dysfunction of this pathway develops during the development of hyperglycemia and μmol/L to diabetes-associated vascular complications. Intraperitoneal (IP) 3-MP (1 mg/kg) raised plasma H2S levels in rats. 3-MP (10 1 mmol/L) promoted angiogenesis in vitro in bEnd3 microvascular endothelial cells and in vivo in a Matrigel assay in mice (0.3-1 mg/kg). In vitro studies with bEnd3 cell homogenates demonstrated that the 3-MP-induced increases in H2S production depended on enzymatic activity, although at higher concentrations (1-3 mmol/L) there was also evidence for an additional nonenzymatic H2S production by 3-MP. In vivo, 3-MP facilitated wound healing in rats, induced the relaxation of dermal microvessels and increased mitochondrial bioenergetic function. In vitro hyperglycemia or in vivo streptozotocin diabetes impaired angiogenesis, attenuated mitochondrial function and delayed wound healing; all of these responses were associated with an impairment of the proangiogenic and bioenergetic effects of 3-MP. The antioxidants DL-α-lipoic acid (LA) in vivo, or dihydrolipoic acid (DHLA) in vitro restored the ability of 3-MP to stimulate angiogenesis, cellular bioenergetics and wound healing in hyperglycemia and diabetes. We conclude that diabetes leads to an impairment of the 3-MST/H2S pathway, and speculate that this may contribute to the pathogenesis of hyperglycemic endothelial cell dysfunction. We also suggest that therapy with H2S donors, or treatment with the combination of 3-MP and lipoic acid may be beneficial in improving angiogenesis and bioenergetics in hyperglycemia.
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Ciro
authors.initials: C
authors.lastname: Coletta
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Katalin
authors.initials: K
authors.lastname: Módis
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Szczesny
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Attila
authors.initials: A
authors.lastname: Brunyánszki
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Gábor
authors.initials: G
authors.lastname: Oláh
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Ester C S
authors.initials: EC
authors.lastname: Rios
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yanagi
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Akbar
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Faculty of Pharmacy, University of Athens, Greece.
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
mesh_terms: D000818:Animals; D002460:Cell Line; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D003545:Cysteine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D006862:Hydrogen Sulfide / Q000097:blood / Q000378:metabolism*; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010101:Oxygen Consumption; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D013466:Sulfurtransferases / Q000235:genetics / Q000378:metabolism*; D008063:Thioctic Acid / Q000494:pharmacology; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D014665:Vasodilator Agents; C008366:3-mercaptopyruvic acid; D008063:Thioctic Acid; D051057:Proto-Oncogene Proteins c-akt; D017869:Cyclic GMP-Dependent Protein Kinases; D013466:Sulfurtransferases; C021550:3-mercaptopyruvate sulphurtransferase; D003545:Cysteine; D006862:Hydrogen Sulfide