Abstract
In platelets, group IVA cytosolic phospholipase A2 (cPLA2α) has been implicated as a key regulator in the hydrolysis of platelet membrane phospholipids, leading to pro-thrombotic thromboxane A2 and anti-thrombotic 12-(S)-hydroxyeicosatetranoic acid production. However, studies using cPLA2α-deficient mice have indicated that other PLA2(s) may also be involved in the hydrolysis of platelet glycerophospholipids. In this study, we found that group VIB Ca2+-independent PLA2 (iPLA2γ)-deficient platelets showed decreases in adenosine diphosphate (ADP)-dependent aggregation and ADP- or collagen-dependent thromboxane A2 production. Electrospray ionization mass spectrometry analysis of platelet phospholipids revealed that fatty acyl compositions of ethanolamine plasmalogen and phosphatidylglycerol were altered in platelets from iPLA2γ-null mice. Furthermore, mice lacking iPLA2γ displayed prolonged bleeding times and were protected against pulmonary thromboembolism. These results suggest that iPLA2γ is an additional, long-sought-after PLA2 that hydrolyzes platelet membranes and facilitates platelet aggregation in response to ADP.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Diphosphate / metabolism
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Animals
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Blood Platelets / metabolism*
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Calcium / metabolism
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Collagen / metabolism
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Disease Susceptibility
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Group VI Phospholipases A2 / deficiency
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Group VI Phospholipases A2 / genetics
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Group VI Phospholipases A2 / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Phospholipids / analysis
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Platelet Activation
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Platelet Aggregation
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Receptors, Purinergic P2Y / metabolism
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Serotonin / metabolism
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Signal Transduction
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Spectrometry, Mass, Electrospray Ionization
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Thrombosis / metabolism
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Thrombosis / pathology
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Thromboxane A2 / metabolism
Substances
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Phospholipids
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Receptors, Purinergic P2Y
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Serotonin
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Thromboxane A2
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Adenosine Diphosphate
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Collagen
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Group VI Phospholipases A2
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Calcium
Grants and funding
This work was in part by a Grant-in-Aid for Scientific Research (B) (21390036 and 25293033) and a Grant-in-Aid for Research Activity start-up (21890254) from the Japan Society for the Promotion of Science; by a Grant-in-Aid for Scientific Research on Innovative Areas (25116720) and a grant for Private University High Technology Research Center Project from the Ministry of Education, Sports, Science, Culture and Technology of Japan; and by a grant from the Terumo Life Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.