Single atom substitution in mouse protein kinase G eliminates oxidant sensing to cause hypertension

• Published in: Nature medicine Vol. 18; no. 2; pp. 286 - 290
• Main Authors: Prysyazhna, Oleksandra, Rudyk, Olena, Eaton, Philip
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2012; Nature Publishing Group
• Subjects: 631/443/1338/1872; 692/699/75; Acetylcholine - pharmacology; Amino acids; Animals; Atoms & subatomic particles; Biological Factors - physiology; Biomedical and Life Sciences; Biomedicine; Blood pressure; Blood Pressure - drug effects; Blood Pressure - physiology; Cancer Research; Care and treatment; Cyclic GMP-Dependent Protein Kinase Type I; Cyclic GMP-Dependent Protein Kinases - genetics; Cyclic GMP-Dependent Protein Kinases - physiology; Development and progression; Electromyography; Endothelium; Epoprostenol - physiology; Heart diseases; Heart Rate - drug effects; Hydrogen peroxide; Hydrogen Peroxide - pharmacology; Hypertension; Hypertension - genetics; Hypertension - physiopathology; Infectious Diseases; letter; Male; Membrane Potentials - drug effects; Metabolic Diseases; Mice; Mice, Inbred C57BL; Molecular Medicine; Mutagenesis, Site-Directed; Myocardial infarction; Neurosciences; NG-Nitroarginine Methyl Ester - pharmacology; Nitric oxide; Nitric Oxide - physiology; Oxidation; Oxidizing agents; Properties; Protein kinases; Proteins; Risk factors; Rodents; Signal Transduction; Sulfur; Vasodilation - drug effects; United Kingdom
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2603

Using mice with an amino substitution in the kinase PKG, a key regulator of blood vessel tone, Oleksandra Prysyazhna et al . provide evidence for the physiological importance of PKG oxidation and disulfide formation in maintaining normal blood pressure. These results clarify the nature of an enigmatic vasodilatory activity termed endothelium-derived hyperpolarizing factor and suggest that vascular oxidative stress can have blood pressure-lowering effects. 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 1 , 2 , 3 , 4 . Hydrogen peroxide (H 2 O 2 ) has been shown to be a major component of EDHF in several vascular beds in multiple species, including in humans 5 , 6 , 7 , 8 , 9 , 10 . H 2 O 2 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 11 . 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 H 2 O 2 on resistance vessels and resulted in hypertension in vivo .