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Mechanistic role of cytochrome P450 monooxygenases in oxidized low-density lipoprotein-induced vascular injury

Therapy through LOX-1 receptor antagonism?
: Thum, T.; Borlak, J.


Circulation research. Journal of the American Heart Association 94 (2004), Nr.1, S.E1-E13
ISSN: 0009-7330
ISSN: 0931-6876
Fraunhofer ITEM ()
endothelial dysfunction; endothelial-derived hyperpolarization factor; oxidized low-density lipoprotein; cytochrome P450 mono-oxygenase; arachidonic acid; Cytochrome P-450

Oxidized low-density lipoprotein (oxLDL) is an important risk factor for vascular injury. Its role on coronary vasoconstriction remains speculative. Endothelial monooxygenases (cytochrome P450s [CYPs]) are regulators of vascular tonus through production of epoxy fatty acids. We investigated the effects of oxLDL on CYP monooxygenases in human arterial coronary endothelial cells and explanted healthy and atherosclerotic aortae. We found oxLDL to induce radical oxygen species production via the action of NADPH oxidase NOX4. Intracellular radical oxygen species production prompted reduced protein expression of the transcriptional regulator nuclear factor 1 (NF-1). We identified novel DNA binding sites for NF-1 in promoter regions of CYPs. DNA binding of NF-1 was confirmed by electromobility shift assays. OxLDL repressed DNA binding of NF-1 and diminished transcript level of CYP genes targeted by this factor. The production of endothelial-derived hyperpolarization factor, a key regulator of vascular tonus, was also reduced. Repression of CYP monooxygenases was reversed, and production of endothelial-derived hyperpolarization factor was normalized after treatment of endothelium with the lectin-like oxLDL receptor antagonist kappa-carrageenan or blocking of LOX-1 with a specific antibody. This suggests a mechanistic role of CYP monooxygenases in oxLDL-induced vascular injury. Therapy of endothelial dysfunction through LOX-1 receptor antagonism will be an interesting avenue to explore.