This Article Full Text Full Text (PDF) All Versions of this Article: 94/1/e1    most recent 01.RES.0000110081.03480.E9v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thum, T. Articles by Borlak, J. Search for Related Content PubMed PubMed Citation Articles by Thum, T. Articles by Borlak, J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CARRAGEENAN GUM MALONALDEHYDE NITRIC OXIDE Related Collections Gene expression Oxidant stress Endothelium/vascular type/nitric oxide Other Vascular biology

Mechanistic Role of Cytochrome P450 Monooxygenases in Oxidized Low-Density Lipoprotein–Induced Vascular Injury

Therapy Through LOX-1 Receptor Antagonism?

From the Center of Drug Research and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany.

Correspondence to Dr Jürgen Borlak, Fraunhofer Institute of Toxicology and Experimental Medicine, Center for Drug Research and Medical Biotechnology, Nikolai-Fuchs-Str. 1, D-30659 Hannover, Germany. E-mail Borlak{at}item.fraunhofer.de

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 -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. The full text of this article is available online at http://www.circresaha.org.

Key Words: endothelial dysfunction • endothelial-derived hyperpolarization factor • arachidonic acid • oxidized low-density lipoprotein • cytochrome P450 monooxygenases

This article has been cited by other articles:

				S. R. Datla, H. Peshavariya, G. J. Dusting, K. Mahadev, B. J. Goldstein, and F. Jiang Important Role of Nox4 Type NADPH Oxidase in Angiogenic Responses in Human Microvascular Endothelial Cells In Vitro Arterioscler Thromb Vasc Biol, November 1, 2007; 27(11): 2319 - 2324. [Abstract] [Full Text] [PDF]

				J.-M. Li and A. M Shah Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2004; 287(5): R1014 - R1030. [Abstract] [Full Text] [PDF]