15-deoxy-[delta]12,14-prostaglandin J2 reinforces the anti-inflammatory capacity of endothelial cells with a genetically determined NO deficit
Rationale:Fluid shear stress (FSS) maintains NOS-3 (endothelial NO synthase) expression. Homozygosity for the C variant of the T-786C single-nucleotide polymorphism of the NOS3 gene, which solely exists in humans, renders the gene less sensitive to FSS, resulting in a reduced endothelial cell (EC) c...
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| Hauptverfasser: | , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
19 Jun 2019
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| In: |
Circulation research
Year: 2019, Jahrgang: 125, Heft: 3, Pages: 282-294 |
| ISSN: | 1524-4571 |
| DOI: | 10.1161/CIRCRESAHA.118.313820 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1161/CIRCRESAHA.118.313820 Verlag, lizenzpflichtig, Volltext: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.313820 
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| Verfasserangaben: | Urban Ivelina, Turinsky Martin, Gehrmann Sviatlana, Morgenstern Jakob, Brune Maik, Milewski Moritz R., Wagner Andreas H., Rumig Cordula, Fleming Thomas, Leuschner Florian, Gleissner Christian A., and Hecker Markus |
MARC
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| 245 | 1 | 0 | |a 15-deoxy-[delta]12,14-prostaglandin J2 reinforces the anti-inflammatory capacity of endothelial cells with a genetically determined NO deficit |c Urban Ivelina, Turinsky Martin, Gehrmann Sviatlana, Morgenstern Jakob, Brune Maik, Milewski Moritz R., Wagner Andreas H., Rumig Cordula, Fleming Thomas, Leuschner Florian, Gleissner Christian A., and Hecker Markus |
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| 246 | 3 | 3 | |a 15-deoxy-delta 12,14-prostaglandin J 2 reinforces the anti-inflammatory capacity of endothelial cells with a genetically determined NO deficit |
| 264 | 1 | |c 19 Jun 2019 | |
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| 500 | |a Im Titel ist [delta] als griechischer Buchstabe dargestellt | ||
| 500 | |a Im Titel ist die Zahl 2 bei J2 tiefgestellt | ||
| 500 | |a Gesehen am 22.04.2020 | ||
| 520 | |a Rationale:Fluid shear stress (FSS) maintains NOS-3 (endothelial NO synthase) expression. Homozygosity for the C variant of the T-786C single-nucleotide polymorphism of the NOS3 gene, which solely exists in humans, renders the gene less sensitive to FSS, resulting in a reduced endothelial cell (EC) capacity to generate NO. Decreased bioavailability of NO in the arterial vessel wall facilitates atherosclerosis. Consequently, individuals homozygous for the C variant have an increased risk for coronary heart disease (CHD).Objective:At least 2 compensatory mechanisms seem to minimize the deleterious effects of this single-nucleotide polymorphism in affected individuals, one of which is characterized herein.Methods and Results:Human genotyped umbilical vein ECs and THP-1 monocytes were used to investigate the role of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) in vitro. Its concentration in plasma samples from genotyped patients with CHD and age-matched CHD-free controls was determined using quantitative ultraperformance LC-MS/MS. Exposure of human ECs to FSS effectively reduced monocyte transmigration particularly through monolayers of CC-genotype ECs. Primarily in CC-genotype ECs, FSS elicited a marked rise in COX (cyclooxygenase)-2 and L-PGDS (lipocalin-type prostaglandin D synthase) expression, which appeared to be NO sensitive, and provoked a significant release of 15d-PGJ2 over baseline. Exogenous 15d-PGJ2 significantly reduced monocyte transmigration and exerted a pronounced anti-inflammatory effect on the transmigrated monocytes by downregulating, for example, transcription of the IL (interleukin)-1β gene (IL1B). Reporter gene analyses verified that this effect is due to binding of Nrf2 (nuclear factor [erythroid-derived 2]-like 2) to 2 AREs (antioxidant response elements) in the proximal IL1B promoter. In patients with CHD, 15d-PGJ2 plasma levels were significantly upregulated compared with age-matched CHD-free controls, suggesting that this powerful anti-inflammatory prostanoid is part of an endogenous defence mechanism to counteract CHD.Conclusions:Despite a reduced capacity to form NO, CC-genotype ECs maintain a robust anti-inflammatory phenotype through an enhanced FSS-dependent release of 15d-PGJ2. | ||
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