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

Taras Afonyushkin,Olga V Oskolkova,Valery N Bochkov

doi:10.1007/s10456-017-9590-5

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.

Highlights

Stem cell factor (SCF, KIT ligand, steel factor) is a growth factor activating receptor tyrosine kinase c-Kit, which is structurally related to the platelet-derived growth factor (PDGF) receptor and is widely recognized for its role in stem cell biology [1]
One of physiologically important genes that were upregulated by oxidized palmitoyl-arachidonoyl-phosphatidylcholine (OxPAPC) in human carotid artery ECs (HCAECs) was KIT ligand (KITL), more often referred to as stem cell factor (SCF)
Elevation of SCF mRNA levels in HCAECs was observed in three independent experiments (Fig. 1a)

Summary

Introduction

Stem cell factor (SCF, KIT ligand, steel factor) is a growth factor activating receptor tyrosine kinase c-Kit, which is structurally related to the platelet-derived growth factor (PDGF) receptor and is widely recognized for its role in stem cell biology [1]. SCF produced in bone marrow by endothelial and perivascular stromal cells is a major player in forming a niche for c-Kit-positive hematopoietic stem cells [2]. SCF and c-Kit are important for differentiation and function of mast cells [3] and demonstrate multiple other biological activities. Rapidly accumulating data point to the role of SCF/c-Kit in regulation of vascular wall homeostasis, which is less investigated as compared to other effects of SCF and c-Kit. Major vascular wall cells such as endothelial cells (EC) and vascular smooth muscle cells (VSMC) are both producers and targets of SCF [4,5,6,7,8]. SCF and c-Kit protect VSMCs from apoptosis [11] and regulate contractile phenotype of these cells [5]

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