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Angiogenesis. 2018 May;21(2):229-236. doi: 10.1007/s10456-017-9590-5. Epub 2018 Jan 12.

Oxidized phospholipids stimulate production of stem cell factor via NRF2-dependent mechanisms.

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25-3, 1090, Vienna, Austria.
2
Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria.
3
Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Humboldtstrasse 46/III, 8010, Graz, Austria.
4
Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Humboldtstrasse 46/III, 8010, Graz, Austria. valery.bochkov@uni-graz.at.
5
Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria. valery.bochkov@uni-graz.at.

Abstract

Receptor tyrosine kinase c-Kit and its ligand stem cell factor (SCF) regulate resident vascular wall cells and recruit circulating progenitors. We tested whether SCF may be induced by oxidized palmitoyl-arachidonoyl-phosphatidylcholine (OxPAPC) known to accumulate in atherosclerotic vessels. Gene expression analysis demonstrated OxPAPC-induced upregulation of SCF mRNA and protein in different types of endothelial cells (ECs). Elevated levels of SCF mRNA were observed in aortas of ApoE-/- knockout mice. ECs produced biologically active SCF because conditioned medium from OxPAPC-treated cells stimulated activation (phosphorylation) of c-Kit in naïve ECs. Induction of SCF by OxPAPC was inhibited by knocking down transcription factor NRF2. Inhibition or stimulation of NRF2 by pharmacological or molecular tools induced corresponding changes in SCF expression. Finally, we observed decreased levels of SCF mRNA in aortas of NRF2 knockout mice. We characterize OxPLs as a novel pathology-associated stimulus inducing expression of SCF in endothelial cells. Furthermore, our data point to transcription factor NRF2 as a major mediator of OxPL-induced upregulation of SCF. This mechanism may represent one of the facets of pleiotropic action of NRF2 in vascular wall.

KEYWORDS:

Atherosclerosis; Electrophilic stress response; NRF2; Oxidized phospholipids; SCF; c-Kit

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