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.
Highlights
Platelets play a key role in hemostasis through their ability to respond to vascular injury
Previous reports showed that iPLA2c-KO mice had abnormal mitochondria in skeletal muscle, myocardium and brain [23,29], mitochondrial architecture was virtually normal in iPLA2c null mouse platelets
The present study has revealed that iPLA2c, one of the Ca2+-independent intracellular phospholipase A2 (PLA2) enzymes, represents the missing link; it is responsible for stimulus-dependent arachidonic acid (AA) release and functions as a key enzyme in platelet aggregation in vitro and thrombus formation in vivo
Summary
Platelets play a key role in hemostasis through their ability to respond to vascular injury. When circulating platelets are exposed to collagen-rich subendothelium at the site of a vascular injury, platelets become activated, release granule contents, and generate thrombin and the lipid mediator thromboxane A2 (TXA2) [1,2]. TXA2 is a potent platelet agonist and an arachidonic acid (AA) metabolite, produced via the cyclooxygenase (COX) pathway [4,5]. Another platelet-derived lipid mediator, 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), is an AA metabolite produced via platelet-type 12-lipoxygenase and acts as a platelet antagonist [6,7]. TXA2 formation is rapid and quickly reaches a plateau in activated platelets, whereas 12(S)HETE formation is slower and continues to increase over a longer period of time
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