Inherited human group IVA cytosolic phospholipase A2 deficiency abolishes platelet, endothelial, and leucocyte eicosanoid generation

Kirkby, N S; Reed, D M; Edin, M L; Rauzi, F; Mataragka, S; Vojnovic, I; Bishop-Bailey, D; Milne, G L; Longhurst, H; Zeldin, D C; Mitchell, J A; Warner, T D

Abstract

Eicosanoids are important vascular regulators, but the phospholipase A2 (PLA2) isoforms supporting their production within the cardiovascular system are not fully understood. To address this, we have studied platelets, endothelial cells, and leukocytes from 2 siblings with a homozygous loss-of-function mutation in group IVA cytosolic phospholipase A2 (cPLA2α). Chromatography/mass spectrometry was used to determine levels of a broad range of eicosanoids produced by isolated vascular cells, and in plasma and urine. Eicosanoid release data were paired with studies of cellular function. Absence of cPLA2α almost abolished eicosanoid synthesis in platelets (e.g., thromboxane A2, control 20.5 ± 1.4 ng/ml vs. patient 0.1 ng/ml) and leukocytes [e.g., prostaglandin E2 (PGE2), control 21.9 ± 7.4 ng/ml vs. patient 1.9 ng/ml], and this was associated with impaired platelet activation and enhanced inflammatory responses. cPLA2α-deficient endothelial cells showed reduced, but not absent, formation of prostaglandin I2 (prostacyclin; control 956 ± 422 pg/ml vs. patient 196 pg/ml) and were primed for inflammation. In the urine, prostaglandin metabolites were selectively influenced by cPLA2α deficiency. For example, prostacyclin metabolites were strongly reduced (18.4% of control) in patients lacking cPLA2α, whereas PGE2 metabolites (77.8% of control) were similar to healthy volunteer levels. These studies constitute a definitive account, demonstrating the fundamental role of cPLA2α to eicosanoid formation and cellular responses within the human circulation.

Citation

Kirkby, N. S., Reed, D. M., Edin, M. L., Rauzi, F., Mataragka, S., Vojnovic, I., …Warner, T. D. (2015). Inherited human group IVA cytosolic phospholipase A2 deficiency abolishes platelet, endothelial, and leucocyte eicosanoid generation. FASEB Journal, 29(11), 4568-4578. https://doi.org/10.1096/fj.15-275065

• Journal Article Type: Article
• Acceptance Date: Jul 6, 2015
• Publication Date: Jul 16, 2015
• Deposit Date: Aug 12, 2015
• Publicly Available Date: Feb 18, 2019
• Journal: FASEB JOURNAL
• Print ISSN: 0892-6638
• Publisher: Federation of American Society of Experimental Biology (FASEB)
• Peer Reviewed: Peer Reviewed
• Volume: 29
• Issue: 11
• Pages: 4568-4578
• DOI: https://doi.org/10.1096/fj.15-275065
• Public URL: https://rvc-repository.worktribe.com/output/1400164