Protein kinase G oxidation is a major cause of injury during sepsis

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 wildtype mice induced oxidative activation of cGMP-dependent protein kinase 1 alpha (PKG I alpha), 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 I alpha oxidative activation in injury is supported by oxidation-resistant Cys42Ser PKG I alpha knock-in mice being markedly protected from these clinical indices of injury during sepsis. We conclude that oxidative activation of PKG I alpha is a key mediator of hypotension and consequential organ injury during sepsis.