title: Single atom substitution in mouse protein kinase G eliminates oxidant sensing to cause hypertension.
abstract: Blood pressure regulation is crucial for the maintenance of health, and hypertension is a risk factor for myocardial infarction, heart failure, stroke and renal disease. Nitric oxide (NO) and prostacyclin trigger well-defined vasodilator pathways; however, substantial vasorelaxation in response to agents such as acetylcholine persists when the synthesis of these molecules is prevented. This remaining vasorelaxation activity, termed endothelium-derived hyperpolarizing factor (EDHF), is more prevalent in resistance than in conduit blood vessels and is considered a major mechanism for blood pressure control. Hydrogen peroxide (H2O2) has been shown to be a major component of EDHF in several vascular beds in multiple species, including in humans. H2O2 causes the formation of a disulfide bond between the two α subunits of protein kinase G I-α (PKGI-α), which activates the kinase independently of the NO-cyclic guanosine monophosphate (cGMP) pathway and is coupled to vasodilation. To test the importance of PKGI-α oxidation in the EDHF mechanism and blood pressure control in vivo, we generated a knock-in mouse expressing only a C42S 'redox-dead' version of PKGI-α. This amino acid substitution, a single-atom change (an oxygen atom replacing a sulfur atom), blocked the vasodilatory action of H2O2 on resistance vessels and resulted in hypertension in vivo.
authors.affiliation: King's College London, Cardiovascular Division, British Heart Foundation Centre of Excellence, Rayne Institute, St Thomas' Hospital, London, UK.
authors.forename: Oleksandra
authors.initials: O
authors.lastname: Prysyazhna
authors.forename: Olena
authors.initials: O
authors.lastname: Rudyk
authors.forename: Philip
authors.initials: P
authors.lastname: Eaton
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics* / Q000502:physiology; D004576:Electromyography; D011464:Epoprostenol / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D015398:Signal Transduction; D014664:Vasodilation / Q000187:drug effects
chemical_list: D001685:Biological Factors; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D011464:Epoprostenol; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569718:PRKG1 protein, human; C569720:Prkg1 protein, mouse; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester