Vascular function of the Cytochrome P450 reductase (POR)

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Oxidative stress caused by imbalanced reactive oxygen species (ROS) is being seen as a strong contributor to cardiovascular diseases (CVD). NADPH oxidase enzymes (Nox) are sources of ROS. Their role in CVD emerged from studies using transgenic animals, unspecific inhibitors but largely from NADPH-stimulated assays. In these assays, membranes isolated from cell or tissue were supplemented with NADPH to recapitulate Nox activity in vitro. Such assays, however, were shown by the applicant not to measure Nox but cytochrome P450 reductase (POR) activity. This enzyme shares structural similarities with Nox enzymes and the vascular effects, which were attributed to Nox enzymes, are potentially mediated by POR. Thus, by an (un)lucky coincidence between POR and Noxes, the later emerged as an important source of oxidative stress in CVD and thus became a pharmacological target, whereas the other enzyme was largely neglected. In the current application, the vascular function of POR and its contribution to assay signal will be identified using transgenic animals, cell culture studies and biochemical assays.