Oxidant-induced activation of protein kinase A: from biochemistry to the cardiovascular physiology of a novel 'redox-dead' knock-in mouse

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Free radicals and oxidising chemicals are produced in cells and tissues. Historically these have been primarily associated with disease or dysfunction. However, over the past decade there has been a growing realisation that these species are not always harmful, and in fact they can play important regulatory roles. We have found in preliminary studies that a protein (known as protein kinase A), which is very important for how the heart is regulated is chemically modified by oxidants and this directly activates it. Here we outline studies that will help fully define the importance of this modification and activation of protein kinase A, both in health and in disease. We will utilise many experimental approaches in this work, including generation of a genetically modified mouse that has been altered so that it cannot be oxidised and directly activated by oxidants. The availability of such mice would be an invaluable resource that will allow us to study fully the importance of oxidant-induced protein kinase A activation in cells, tissues, organs and the animal as a whole.