ATF4-dependent transcription is a key mechanism in VEGF up-regulation by oxidized phospholipids: critical role of oxidized sn-2 residues in activation of unfolded protein response

Oskolkova, Olga; Afonyushkin, Taras; Leitner, Alexander; Schlieffen, Elena von; Gargalovic, Peter S.; Lusis, Aldons J.; Binder, Bernd R.; Bochkov, Valery N.

doi:10.1182/blood-2007-09-112870

Cited by 96 publications

(89 citation statements)

References 64 publications

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“…Mass-spectra of OxPLs have been published previously (21). 1-Palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC), a mixture of 1-palmitoyl-2-(12-hydroperoxyeicosa-5,8,10,14-tetraenoyl)-sn-glycero-3-phosphocholine and 1-palmitoyl-2-(15-hydroperoxyeicosa-5,8,11,13-tertraenoyl)-sn-glycero-3-phosphocholine (PAPC-OOH), and 1-palmitoyl-2-(5,6-epoxy isoprostane E2)-sn-glycero-3-phosphocholine (PEIPC)-enriched fraction were prepared as described previously (25). Noncleavable analogue of PAPC was synthesized as described previously (21).…”

Section: Methodsmentioning

confidence: 99%

Oxidized Phospholipids Are More Potent Antagonists of Lipopolysaccharide than Inducers of Inflammation

Oskolkova¹,

Afonyushkin²,

Preinerstorfer

et al. 2010

The Journal of Immunology

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112

109

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Polyunsaturated fatty acids are precursors of multiple pro- and anti-inflammatory molecules generated by enzymatic stereospecific and positionally specific insertion of oxygen, which is a prerequisite for recognition of these mediators by cellular receptors. However, nonenzymatically oxidized free and esterified polyunsaturated fatty acids also demonstrate activities relevant to inflammation. In particular, phospholipids containing oxidized fatty acid residues (oxidized phospholipids; OxPLs) were shown to induce proinflammatory changes in endothelial cells but paradoxically also to inhibit inflammation induced via TLR4. In this study, we show that half-maximal inhibition of LPS-induced elevation of E-selectin mRNA in endothelial cells developed at concentrations of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) 10-fold lower than those required to induce proinflammatory response. Similar concentration difference was observed for other classes and molecular species of OxPLs. Upon injection into mice, OxPAPC did not elevate plasma levels of IL-6 and keratinocyte chemoattractant but strongly inhibited LPS-induced upregulation of these inflammatory cytokines. Thus, both in vitro and in vivo, anti-LPS effects of OxPLs are observed at lower concentrations than those required for their proinflammatory action. Quantification of the most abundant oxidized phosphatidylcholines by HPLC/tandem mass spectrometry showed that circulating concentrations of total oxidized phosphatidylcholine species are close to the range where they demonstrate anti-LPS activity but significantly lower than that required for induction of inflammation. We hypothesize that low levels of OxPLs in circulation serve mostly anti-LPS function and protect from excessive systemic response to TLR4 ligands, whereas proinflammatory effects of OxPLs are more likely to develop locally at sites of tissue deposition of OxPLs (e.g., in atherosclerotic vessels).

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Section: Methodsmentioning

confidence: 99%

Oxidized Phospholipids Are More Potent Antagonists of Lipopolysaccharide than Inducers of Inflammation

Oskolkova¹,

Afonyushkin²,

Preinerstorfer

et al. 2010

The Journal of Immunology

Self Cite

112

109

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“…Further, immunohistochemical analysis of human atherosclerotic lesions indicated activation of the unfolded protein response in areas containing oxPLs [186]. Importantly, it has also been reported that up-regulation of IL-8 and MCP-1 expression induced by oxPLs is independent of the classical NF-B pathway, but that it involves activation of c-Src kinase.…”

Section: Up-regulation Of Chemokines Inflammatory Cytokines and Growmentioning

confidence: 99%

“…A later study found that oxPLs induced upregulation of VEGF by activating transcription factor 4 (ATF4)-dependent transcription [186].…”

Section: Effects On Endothelial Cellsmentioning

confidence: 99%

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Inflammation-related gene expression by lipid oxidation-derived products in the progression of atherosclerosis

Leonarduzzi

Gamba

Gargiulo

et al. 2012

Free Radical Biology and Medicine

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“…1 Although these authors never explicitly stated that theirs was the first and only study demonstrating that VEGF-A is ATF4-responsive, they failed to acknowledge the contributions of 4 previous publications demonstrating regulation of VEGF-A by ATF4. [1][2][3][4][5] Although the authors stated that the existence of an ATF4 binding site in the VEGF-A gene was previously demonstrated, they neglected to mention that any previous study had ever established a role of ATF4 in the control of VEGF-A transcription. Furthermore, an accompanying review by Chin …”

Section: Regulation Of Vascular Endothelial Growth Factor a By Activamentioning

confidence: 99%

Regulation of Vascular Endothelial Growth Factor A by Activating Transcription Factor 4

Abcouwer

Roybal²

2008

Circulation Research

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ATF4-dependent transcription is a key mechanism in VEGF up-regulation by oxidized phospholipids: critical role of oxidized sn-2 residues in activation of unfolded protein response

Cited by 96 publications

References 64 publications

Oxidized Phospholipids Are More Potent Antagonists of Lipopolysaccharide than Inducers of Inflammation

Oxidized Phospholipids Are More Potent Antagonists of Lipopolysaccharide than Inducers of Inflammation

Inflammation-related gene expression by lipid oxidation-derived products in the progression of atherosclerosis

Regulation of Vascular Endothelial Growth Factor A by Activating Transcription Factor 4

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