title: Inherited human group IVA cytosolic phospholipase A2 deficiency abolishes platelet, endothelial, and leucocyte eicosanoid generation.
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.
authors.affiliation: *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.affiliation: *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Reed
authors.affiliation: *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.affiliation: *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rauzi
authors.affiliation: *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom.
authors.forename: Stefania
authors.initials: S
authors.lastname: Mataragka
authors.affiliation: *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom.
authors.forename: Ivana
authors.initials: I
authors.lastname: Vojnovic
authors.affiliation: *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Bishop-Bailey
authors.affiliation: *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom.
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.affiliation: *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom.
authors.forename: Hilary
authors.initials: H
authors.lastname: Longhurst
authors.affiliation: *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
authors.affiliation: *National Heart and Lung Institute, Imperial College London, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom; Department of Pharmacology and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA; and Immunology Department, Barts Health and the London National Health Service Trust, London, United Kingdom t.d.warner@qmul.ac.uk.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
mesh_terms: D000328:Adult; D016824:Antigens, Human Platelet / Q000235:genetics*; D001792:Blood Platelets / Q000201:enzymology* / Q000473:pathology; D015232:Dinoprostone / Q000096:biosynthesis / Q000235:genetics*; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D011464:Epoprostenol / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000201:enzymology* / Q000473:pathology; D008297:Male; D009154:Mutation; D015539:Platelet Activation / Q000235:genetics
chemical_list: D016824:Antigens, Human Platelet; C083451:human platelet antigen 1b; D011464:Epoprostenol; D015232:Dinoprostone
keywords: cardiovascular; inflammation; prostacyclin; thromboxane A2