Group VIB Calcium-Independent Phospholipase A(2) (iPLA(2)γ) Regulates Platelet Activation, Hemostasis and Thrombosis in Mice

In platelets, group IVA cytosolic phospholipase A(2) (cPLA(2)α) has been implicated as a key regulator in the hydrolysis of platelet membrane phospholipids, leading to pro-thrombotic thromboxane A(2) and anti-thrombotic 12-(S)-hydroxyeicosatetranoic acid production. However, studies using cPLA(2)α-deficient mice have indicated that other PLA(2)(s) may also be involved in the hydrolysis of platelet glycerophospholipids. In this study, we found that group VIB Ca(2+)-independent PLA(2) (iPLA(2)γ)-deficient platelets showed decreases in adenosine diphosphate (ADP)-dependent aggregation and ADP- or collagen-dependent thromboxane A(2) production. Electrospray ionization mass spectrometry analysis of platelet phospholipids revealed that fatty acyl compositions of ethanolamine plasmalogen and phosphatidylglycerol were altered in platelets from iPLA(2)γ-null mice. Furthermore, mice lacking iPLA(2)γ displayed prolonged bleeding times and were protected against pulmonary thromboembolism. These results suggest that iPLA(2)γ is an additional, long-sought-after PLA(2) that hydrolyzes platelet membranes and facilitates platelet aggregation in response to ADP.