Functional interplay of transcriptional activators in the regulation of the cytoprotective human CYP2J2 gene

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Human cytochrome P450 2J2 (CYP2J2) is expressed in many tissues. This enzyme acts on polyunsaturated fatty acids to form epoxides that control ion fluxes, the size of blood vessels and inflammation, and also help cells to survive the damaging effects of oxygen deprivation and other stresses. So CYP2J2 has an important role in both normal and injured cells. Increasing the amount of CYP2J2 in cells may be extremely valuable in the defence against injury. Until recently, however, no treatments have been able to do this but we now know that the biologically important vitamin A derivative all-trans-retinoic acid (ATRA) can increase CYP2J2 in cells. In this project we will build on this novel finding to develop treatments that increase CYP2J2 in tissues. About 10% of people have a variant CYP2J2 gene that differs from the common form by one nucleotide. This polymorphic variant can decrease the amount of the CYP2J2 enzyme and increase cardiovascular risk. We ve found that this polymorphism is located in a critical control region of the gene and affects how the gene responds to transcription factors. The present project will study in detail the regulation of the CYP2J2 gene and its naturally occurring variant by transcription factors that bind to this control region. We will also test how the polymorphic version of the gene responds to stress stimuli and to treatments like ATRA that increase the amount of the wild-type gene in cells. Studying human gene regulation is difficult because we cannot easily measure their levels in individuals. So we will make transgenic mice to study human CYP2J2 regulation and will test whether the treatments we devise in cells also work in vivo. These studies will help us to design pharmacological strategies to increase CYP2J2 in cells. By maintaining the beneficial effects of CYP2J2, and understanding how these are altered in the variant, a significant outcome of the project could be a new treatment of cardiovascular disease.