Discrete Role for Cytosolic Phospholipase A(2)α in Platelets: Studies Using Single and Double Mutant Mice of Cytosolic and Group IIA Secretory Phospholipase A(2)

Among several different types of phospholipase A(2) (PLA(2)), cytosolic PLA(2) (cPLA(2))α and group IIA (IIA) secretory PLA(2) (sPLA(2)) have been studied intensively. To determine the discrete roles of cPLA(2)α in platelets, we generated two sets of genetically engineered mice (cPLA(2)α(−/−)/sPLA(2)-IIA(−/−) and cPLA(2)α(−/−)/sPLA(2)-IIA(+/+)) and compared their platelet function with their respective wild-type C57BL/6J mice (cPLA(2)α(+/+)/sPLA(2)-IIA(−/−)) and C3H/HeN (cPLA(2)α(+/+)/sPLA(2)-IIA(+/+)). We found that cPLA(2)α is needed for the production of the vast majority of thromboxane (TX)A(2) with collagen stimulation of platelets. In cPLA(2)α-deficient mice, however, platelet aggregation in vitro is only fractionally decreased because small amounts of TX produced by redundant phospholipase enzymes sufficiently preserve aggregation. In comparison, adenosine triphosphate activation of platelets appears wholly independent of cPLA(2)α and sPLA(2)-IIA for aggregation or the production of TX, indicating that these phospholipases are specifically linked to collagen receptors. However, the lack of high levels of TX limiting vasoconstriction explains the in vivo effects seen: increased bleeding times and protection from thromboembolism. Thus, cPLA(2)α plays a discrete role in the collagen-stimulated production of TX and its inhibition has a therapeutic potential against thromboembolism, with potentially limited bleeding expected.