Key result
Inherited cPLA2α deficiency almost abolished eicosanoid synthesis in platelets (thromboxane A2 0.1 vs 20.5 ng/ml) and leukocytes (PGE2 1.9 vs 21.9 ng/ml), and reduced endothelial prostacyclin.
Observational (n=2)
cPLA2α plays a fundamental role in eicosanoid formation and cellular responses within the human circulation.
Caution against practice change from one case; supports cPLA2α as central to human eicosanoid synthesis but leaves clinical implications open.
Eicosanoids are important vascular regulators, but the phospholipase A 2 (PLA 2 ) 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 A 2 (cPLA 2 α). 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 cPLA 2 α almost abolished eicosanoid synthesis in platelets ( e.g. , thromboxane A 2 , control 20.5 ±1.4 ng/ml vs. patient 0.1 ng/ml) and leukocytes [ e.g. , prostaglandin E 2 (PGE 2 ), 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. cPLA 2 α‐deficient endothelial cells showed reduced, but not absent, formation of prostaglandin I 2 (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 cPLA 2 α deficiency. For example, prostacyclin metabolites were strongly reduced (18.4% of control) in patients lacking cPLA 2 α, whereas PGE 2 metabolites (77.8% of control) were similar to healthy volunteer levels. These studies constitute a definitive account, demonstrating the fundamental role of cPLA 2 α to eicosanoid formation and cellular responses within the human circulation.—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. Inherited human group IVA cytosolic phospholipase A 2 deficiency abolishes platelet, endothelial, and leucocyte eicosanoid generation. FASEB J. 29, 4568‐4578 (2015). www.fasebj.org
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Kirkby et al. (2015) conducted an observational in Inherited human group IVA cytosolic phospholipase A2 deficiency (n=2). Homozygous loss-of-function mutation in cPLA2α vs. Healthy controls was evaluated on Eicosanoid generation in platelets, endothelial cells, and leukocytes. Inherited cPLA2α deficiency almost abolished eicosanoid synthesis in platelets (thromboxane A2 0.1 vs 20.5 ng/ml) and leukocytes (PGE2 1.9 vs 21.9 ng/ml), and reduced endothelial prostacyclin.
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