title: Protein kinase G oxidation is a major cause of injury during sepsis.
abstract: Sepsis is a common life-threatening clinical syndrome involving complications as a result of severe infection. A cardinal feature of sepsis is inflammation that results in oxidative stress. Sepsis in wild-type mice induced oxidative activation of cGMP-dependent protein kinase 1 alpha (PKG Iα), which increased blood vessel dilation and permeability, and also lowered cardiac output. These responses are typical features of sepsis and their combined effect is a lowering of blood pressure. This hypotension, a hallmark of sepsis, resulted in underperfusion of end organs, resulting in their damage. A central role for PKG Iα oxidative activation in injury is supported by oxidation-resistant Cys42Ser PKG Iα knock-in mice being markedly protected from these clinical indices of injury during sepsis. We conclude that oxidative activation of PKG Iα is a key mediator of hypotension and consequential organ injury during sepsis.
authors.affiliation: Cardiovascular Division, King's College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, United Kingdom.
authors.forename: Olena
authors.initials: O
authors.lastname: Rudyk
authors.forename: Alkystis
authors.initials: A
authors.lastname: Phinikaridou
authors.forename: Oleksandra
authors.initials: O
authors.lastname: Prysyazhna
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Burgoyne
authors.forename: René M
authors.initials: RM
authors.lastname: Botnar
authors.forename: Philip
authors.initials: P
authors.lastname: Eaton
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D007022:Hypotension / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D015151:Immunoblotting; D007770:L-Lactate Dehydrogenase / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009102:Multiple Organ Failure / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D010084:Oxidation-Reduction; D018805:Sepsis / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*
chemical_list: D007770:L-Lactate Dehydrogenase; D062965:Cyclic GMP-Dependent Protein Kinase Type I
keywords: cardiovascular function; endotoxin; redox