title: Extracellular transsulfuration generates hydrogen sulfide from homocysteine and protects endothelium from redox stress.
abstract: Homocysteine, a cardiovascular and neurocognitive disease risk factor, is converted to hydrogen sulfide, a cardiovascular and neuronal protectant, through the transsulfuration pathway. Given the damaging effects of free homocysteine in the blood and the importance of blood homocysteine concentration as a prognosticator of disease, we tested the hypotheses that the blood itself regulates homocysteine-hydrogen sulfide metabolism through transsulfuration and that transsulfuration capacity and hydrogen sulfide availability protect the endothelium from redox stress. Here we show that the transsulfuration enzymes, cystathionine β-synthase and cystathionine γ-lyase, are secreted by microvascular endothelial cells and hepatocytes, circulate as members of the plasma proteome, and actively produce hydrogen sulfide from homocysteine in human blood. We further demonstrate that extracellular transsulfuration regulates cell function when the endothelium is challenged with homocysteine and that hydrogen sulfide protects the endothelium from serum starvation and from hypoxia-reoxygenation injury. These novel findings uncover a unique set of opportunities to explore innovative clinical diagnostics and therapeutic strategies in the approach to homocysteine-related conditions such as atherosclerosis, thrombosis, and dementia.
authors.affiliation: Idaho State Univ., Dept. of Biological Sciences, 921 S 8th Ave. Stop 8007, Pocatello, ID 83209-8007, USA. bearshaw@isu.edu
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Bearden
authors.forename: Richard S
authors.initials: RS
authors.lastname: Beard
authors.forename: Jean C
authors.initials: JC
authors.lastname: Pfau
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism*; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D023421:Models, Animal; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D055815:Young Adult
chemical_list: D006710:Homocysteine; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D003545:Cysteine; D006862:Hydrogen Sulfide
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