15-deoxy-[delta]12,14-prostaglandin J2 reinforces the anti-inflammatory capacity of endothelial cells with a genetically determined NO deficit

• Verfasst von: Urban, Ivelina [VerfasserIn]
• Verfasst von: Turinsky, Martin [VerfasserIn]
• Verfasst von: Gehrmann, Sviatlana [VerfasserIn]
• Verfasst von: Morgenstern, Jakob [VerfasserIn]
• Verfasst von: Brune, Maik [VerfasserIn]
• Verfasst von: Milewski, Moritz R. [VerfasserIn]
• Verfasst von: Wagner, Andreas H. [VerfasserIn]
• Verfasst von: Rumig, Cordula [VerfasserIn]
• Verfasst von: Fleming, Thomas [VerfasserIn]
• Verfasst von: Leuschner, Florian [VerfasserIn]
• Verfasst von: Gleißner, Christian A. [VerfasserIn]
• Verfasst von: Hecker, Markus [VerfasserIn]
• Titel: 15-deoxy-[delta]12,14-prostaglandin J2 reinforces the anti-inflammatory capacity of endothelial cells with a genetically determined NO deficit
• Verf.angabe: 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
• E-Jahr: 2019
• Jahr: 19 Jun 2019
• Umfang: 13 S.
• Fussnoten: Im Titel ist [delta] als griechischer Buchstabe dargestellt ; Im Titel ist die Zahl 2 bei J2 tiefgestellt ; Gesehen am 22.04.2020
• Titel Quelle: Enthalten in: Circulation research
• Ort Quelle: New York, NY : Assoc., 1953
• Jahr Quelle: 2019
• Band/Heft Quelle: 125(2019), 3, Seite 282-294
• ISSN Quelle: 1524-4571
• DOI: doi:10.1161/CIRCRESAHA.118.313820
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1695708741

Abstract

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.