The Journal of Experimental Medicine
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Published online 29 July 2002 doi:10.1084/jem.20011443
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© Rockefeller University Press, 0022-1007/2002/8/349/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 3, August 5, 2002 349-357

Discrete Role for Cytosolic Phospholipase A2{alpha} in Platelets : Studies Using Single and Double Mutant Mice of Cytosolic and Group IIA Secretory Phospholipase A2



Dennis A. Wong, Yoshihiro Kita, Naonori Uozumi and Takao Shimizu

Department of Biochemistry and Molecular Biology, and Core Research and Evolutional Science and Technology, The University of Tokyo, Tokyo 113-0033, Japan

Address correspondence to Takao Shimizu, Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. Phone: 81-3-5802-2925; Fax: 81-3-3813-8732; E-mail: tshimizu{at}m.u-tokyo.ac.jp

Among several different types of phospholipase A2 (PLA2), cytosolic PLA2 (cPLA2){alpha} and group IIA (IIA) secretory PLA2 (sPLA2) have been studied intensively. To determine the discrete roles of cPLA2{alpha} in platelets, we generated two sets of genetically engineered mice (cPLA2{alpha}-/-/sPLA2-IIA-/- and cPLA2{alpha}-/-/sPLA2-IIA+/+) and compared their platelet function with their respective wild-type C57BL/6J mice (cPLA2{alpha}+/+/sPLA2-IIA-/-) and C3H/HeN (cPLA2{alpha}+/+/sPLA2-IIA+/+). We found that cPLA2{alpha} is needed for the production of the vast majority of thromboxane (TX)A2 with collagen stimulation of platelets. In cPLA2{alpha}-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 cPLA2{alpha} and sPLA2-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, cPLA2{alpha} 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.

Key Words: knockout mice • platelet aggregation • bleeding • thromboembolism • thromboxane


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