Involvement of CK2 in activation of electrophilic genes in endothelial cells by oxidized phospholipids

Bernd R Binder,Taras Afonyushkin,Olga V Oskolkova,Valery N Bochkov

doi:10.1194/jlr.m009480

Abstract

Oxidized phospholipids (OxPLs) are increasingly recognized as pleiotropic lipid mediators demonstrating a variety of biological activities. In particular, OxPLs induce electrophilic stress response and stimulate expression of NF-E2-related factor 2 (NRF2)-dependent genes. The mechanisms of NRF2 upregulation in response to OxPLs, however, are incompletely understood. Here we show that upregulation of NRF2 by OxPLs depends on the activity of the CK2 protein kinase. Inactivation of CK2 by chemical inhibitors or gene silencing resulted in diminished accumulation of NRF2 and its target genes, GCLM, HMOX1, and NQO1, downstream in response to OxPLs. Furthermore, inhibition of CK2 suppressed NRF2-dependent induction of ATF4 and its downstream gene VEGF. Thus, inactivation of CK2 in OxPL-treated endothelial cells results in inhibition of the NRF2-ATF4-VEGF axis and is likely to produce antiangiogenic effects. This work characterizes novel cross-talk between CK2 and cellular stress pathways, which may provide additional insights into the mechanisms of beneficial action and side-effects of CK2 inhibitors.

Highlights

Oxidized phospholipids (OxPLs) are increasingly recognized as pleiotropic lipid mediators demonstrating a variety of biological activities
We hypothesized that PI3K is not involved in OxPL-induced upregulation of NF-E2-related factor 2 (NRF2), and that LY294002 may inhibit another protein kinase which is important for induction of electrophilic response by oxidized PAPC (OxPAPC)
The major finding of this study is that full induction by OxPLs of NRF2 and its target genes in venous and arterial endothelial cell (EC) depends on the activity of CK2

Summary

Introduction

Oxidized phospholipids (OxPLs) are increasingly recognized as pleiotropic lipid mediators demonstrating a variety of biological activities. OxPLs induce electrophilic stress response and stimulate expression of NF-E2-related factor 2 (NRF2)-dependent genes. Oxidized phospholipids (OxPLs) contain esterified oxidized residues and are increasingly recognized as pleiotropic lipid messengers demonstrating multiple biological activities including their ability to induce monocytic inflammation, procoagulant shift in endothelium, regulation of endothelial barrier function, and angiogenesis [1]. Electrophilic compounds induce accumulation of NRF2 in the nucleus and activation of transcription of its target genes. In addition to this canonical mechanism of NRF2 activation, several protein kinases such as PERK [5], phosphatidylinositol-3-kinase (PI3K) [6, 7], and CK2 [8, 9] were demonstrated to regulate nuclear accumulation or transcriptional activity of NRF2

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