Redox regulation of cGMP-dependent protein kinase Iα in the cardiovascular system.

Oleksandra Prysyazhna,Philip Eaton

doi:10.3389/fphar.2015.00139

Abstract

Elevated levels of oxidants in biological systems have been historically referred to as “oxidative stress,” a choice of words that perhaps conveys an imbalanced view of reactive oxygen species in cells and tissues. The term stress suggests a harmful role, whereas a contemporary view is that oxidants are also crucial for the maintenance of homeostasis or adaptive signaling that can actually limit injury. This regulatory role for oxidants is achieved in part by them inducing oxidative post-translational modifications of proteins which may alter their function or interactions. Such mechanisms allow changes in cell oxidant levels to be coupled to regulated alterations in enzymatic function (i.e., signal transduction), which enables “redox signaling.” In this review we focus on the role of cGMP-dependent protein kinase (PKG) Ia disulfide dimerisation, an oxidative modification that is induced by oxidants that directly activates the enzyme, discussing how this impacts on the cardiovascular system. Additionally, how this oxidative activation of PKG may coordinate with or differ from classical activation of this kinase by cGMP is also considered.

Highlights

Post-translational modification of proteins is a well-recognized mechanism of regulating their function
The oxidative activation of protein kinase G (PKG) Iα by C42 interprotein disulfide formation is an important mechanism contributing to blood pressure homeostasis, being a component of endotheliumderived hyperpolarizing factor (EDHF)-dependent vasodilation (Figure 2)
Disulfide activation of PKG Iα by dimerization mediates relaxation of bovine coronary arteries to hypoxia, which was associated with oxidation of cytosolic NADPH and phosphorylation of the PKG substrate protein vasodilatorstimulated phosphoprotein (VASP; Neo et al, 2011; Figure 2). These data support PKG Iα oxidation as a mechanism of EDHF-dependent vasodilation, it is notable that the evidence for other factors such as epoxyeicosatrienoic acids (EETs) being a principal mediator is especially robust (Fromel and Fleming, 2015)

Summary

Oleksandra Prysyazhna and Philip Eaton*

Cardiovascular Division, King’s College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas’ Hospital, London, UK. The term stress suggests a harmful role, whereas a contemporary view is that oxidants are crucial for the maintenance of homeostasis or adaptive signaling that can limit injury This regulatory role for oxidants is achieved in part by them inducing oxidative post-translational modifications of proteins which may alter their function or interactions. In this review we focus on the role of cGMP-dependent protein kinase (PKG) Iα disulfide dimerisation, an oxidative modification that is induced by oxidants that directly activates the enzyme, discussing how this impacts on the cardiovascular system How this oxidative activation of PKG may coordinate with or differ from classical activation of this kinase by cGMP is considered

Introduction

The Role of PKG Iα Disulfide Dimerisation in Blood Vessels

The Role of PKG Iα Disulfide Dimerisation in the Heart