Vascular function of the Cytochrome P450 reductase (POR)
Final Report Abstract
Oxidative stress has been linked to cardiovascular disease and cytochrome P450 enzymes (CYP450) are sources of reactive oxygen species (ROS). CYP450 enzymes receive electrons from the cytochrome P450 reductase (POR) which drives their activity. Despite of more than thirty years of research on vascular CYP450, their in vivo function using a pan and subtractive approach was missing due to redundancy in the CYP450 system. POR is coded by a single gene whereas the CYP450 enzymes are coded by more than 50 genes in humans and 90 in mice. Thus, in this application we deleted POR in a cell-specific fashion to study the effect of a total loss of CYP450 activity and its consequence for cardiovascular function. We have successfully generated tamoxifen-inducible, smooth muscle cell (smcPOR-/-) or endothelial cell-specific knockout mice of POR (ecPOR-/-). Deletion of POR in smooth muscle cells induced no changes in vascular function and did not alter the local release of nitric oxide from organic nitrate-based drugs. In contrast, endothelial cell-specific knockout of POR induced endothelial dysfunction, hypertension and cardiac remodelling. Mechanistically, ablation of POR/CYP450 function in endothelial cells reduced nitric oxide synthase (eNOS) activity and led to a metabolic shunt of arachidonic acid: Epoxyeicosatrienic acid lipids (EETs) that support vessel relaxation were reduced in ecPOR-/- mice as compared to control mice whereas cyclooxygenase (COX)-derived prostanoids like prostaglandins (PGD2, PGE2 and PGF2α) and thromboxane that have vasoconstrictor functions were increased. Treatment of hypertensive mice (angiotensin II infusion model, 0.7 mg/kg/day) with naproxen (a non-specific COX inhibitor) selectively reduced blood pressure in ecPOR-/-. Our findings show an importance of endothelial POR/CYP450 for normal cardiovascular function and highlight shunting as a clinically important phenomenon that is not largely studied in the cardiovascular system yet. Furthermore, this study may help understanding why certain polymorphisms of the POR and CYP450 enzymes system are linked to cardiovascular disease.
Publications
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Vascular biotransformation of organic nitrates is independent of cytochrome P450 monooxygenases. British Journal of Pharmacology, 178(7), 1495-1506.
Lopez, Melina; Malacarne, Pedro F.; Gajos‐Draus, Anna; Ding, Xinxin; Daiber, Andreas; Lundberg, Jon O.; Offermanns, Stefan; Brandes, Ralf P. & Rezende, Flávia
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Endothelial deletion of the cytochrome P450 reductase leads to cardiac remodelling. Frontiers in Physiology, 13.
Lopez, Melina; Malacarne, Pedro F.; Ramanujam, Deepak P.; Warwick, Timothy; Müller, Niklas; Hu, Jiong; Dewenter, Matthias; Weigert, Andreas; Günther, Stefan; Gilsbach, Ralf; Engelhardt, Stefan; Brandes, Ralf P. & Rezende, Flávia
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Epoxyeicosatrienoic Acid and Prostanoid Crosstalk at the Receptor and Intracellular Signaling Levels to Maintain Vascular Tone. International Journal of Molecular Sciences, 23(11), 5939.
Malacarne, Pedro Felipe; Bezzenberger, Justus; Lopez, Melina; Warwick, Timothy; Müller, Niklas; Brandes, Ralf P. & Rezende, Flávia
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Loss of Endothelial Cytochrome P450 Reductase Induces Vascular Dysfunction in Mice. Hypertension, 79(6), 1216-1226.
Malacarne, Pedro Felipe; Ratiu, Corina; Gajos-Draus, Anna; Müller, Niklas; Lopez, Melina; Pflüger-Müller, Beatrice; Ding, Xinxin; Warwick, Timothy; Oo, James; Siragusa, Mauro; Angioni, Carlo; Günther, Stefan; Weigert, Andreas; Geißlinger, Gerd; Lütjohann, Dieter; Schunck, Wolf-Hagen; Fleming, Ingrid; Brandes, Ralf P. & Rezende, Flávia
