title: Protein kinase G Iα oxidation paradoxically underlies blood pressure lowering by the reductant hydrogen sulfide.
abstract: Dysregulated blood pressure control leading to hypertension is prevalent and is a risk factor for several common diseases. Fully understanding blood pressure regulation offers the possibility of developing rationale therapies to alleviate hypertension and associated disease risks. Although hydrogen sulfide (H2S) is a well-established endogenous vasodilator, the molecular basis of its blood-pressure lowering action is incompletely understood. H2S-dependent vasodilation and blood pressure lowering in vivo was mediated by it catalyzing formation of an activating interprotein disulfide within protein kinase G (PKG) Iα. However, this oxidative activation of PKG Iα is counterintuitive because H2S is a thiol-reducing molecule that breaks disulfides, and so it is not generally anticipated to induce their formation. This apparent paradox was explained by H2S in the presence of molecular oxygen or hydrogen peroxide rapidly converting to polysulfides, which have oxidant properties that in turn activate PKG by inducing the disulfide. These observations are relevant in vivo because transgenic knockin mice in which the cysteine 42 redox sensor within PKG has been systemically replaced with a redox-dead serine residue are resistant to H2S-induced blood pressure lowering. Thus, a primary mechanism by which the reductant molecule H2S lowers blood pressure is mediated somewhat paradoxically by the oxidative activation of PKG.
authors.affiliation: From the Cardiovascular Division, King's College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London, United Kigdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Stubbert
authors.affiliation: From the Cardiovascular Division, King's College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London, United Kigdom.
authors.forename: Oleksandra
authors.initials: O
authors.lastname: Prysyazhna
authors.affiliation: From the Cardiovascular Division, King's College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London, United Kigdom.
authors.forename: Olena
authors.initials: O
authors.lastname: Rudyk
authors.affiliation: From the Cardiovascular Division, King's College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London, United Kigdom.
authors.forename: Jenna
authors.initials: J
authors.lastname: Scotcher
authors.affiliation: From the Cardiovascular Division, King's College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London, United Kigdom.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Burgoyne
authors.affiliation: From the Cardiovascular Division, King's College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London, United Kigdom. philip.eaton@kcl.ac.uk.
authors.forename: Philip
authors.initials: P
authors.lastname: Eaton
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000378:metabolism*; D004195:Disease Models, Animal; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019163:Reducing Agents
chemical_list: D019163:Reducing Agents; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D006862:Hydrogen Sulfide
keywords: PKGIα; blood pressure; hydrogen sulfide; oxidation-reduction; vasodilation