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April 2022

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Loss of Endothelial Cytochrome P450 Reductase Induces Vascular Dysfunction in Mice. DZHK authors: Pedro Felipe Malacarne, Corina Ratiu, Niklas Müller, Melina Lopez, Beatrice Pflüger-Müller, Timothy Warwick, James Oo, Mauro Siragusa, Ingrid Fleming, Ralf P. Brandes, Flávia Rezende, Hypertension. 2022


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In this study published in Hypertension, we have investigated the contribution of the Cytochrome P450-(CYP450) derived oxylipids for vascular function. Despite of over 30 years of research on these vasoactive lipids, their function is incompletely understood due to the large size of the CYP450 superfamily and the lack of specific pan-CYP inhibitors. To overcome these limitations, we have generated an endothelial cell-specific, tamoxifen inducible knockout mouse of the cytochrome P450 reductase (ecPOR-/-) to functionally switch off all the microsomal CYP450 enzymes.

We found that POR impacts on normal vascular tone by maintaining endothelial nitric oxide synthase (eNOS) activity. Furthermore, production of epoxyeicosatrienoic acids (EETs) was reduced in aorta and lungs of ecPOR-/- as measured by lipidomics (LC-MS/MS).

Conversely, prostanoids such as thromboxane B2 and prostaglandins (D2 and F2α) were increased in tissue of ecPOR-/- as compared to control mice. Mechanistically, inactivation of endothelial CYP shunted arachidonic acid towards cyclooxygenases (COX). Functionally, this potentiated angiotensin II-induced hypertension in vivo, as we could demonstrate by COX inhibition with naproxen: This compound prevented the knockout-mediated potentiation of the hypertension response. The study may therefore help understanding why certain polymorphisms of the POR and CYP system are linked to cardiovascular disease.

Link zum Paper