OBJECTIVE: Several secreted phospholipases A2 (sPLA2s), including group IIA, 
III, V, and X, have been linked to the development of atherosclerosis, which led 
to the clinical testing of A-002 (varespladib), a broad sPLA2 inhibitor for the 
treatment of coronary artery disease. Group X sPLA2 (PLA2G10) has the most 
potent hydrolyzing activity toward phosphatidylcholine and is believed to play a 
proatherogenic role.
METHODS AND RESULTS: Here, we show that Ldlr(-/-) mice reconstituted with bone 
marrow from mouse group X-deficient mice (Pla2g10(-/-)) unexpectedly display a 
doubling of plaque size compared with Pla2g10(+/+) chimeric mice. Macrophages of 
Pla2g10(-/-) mice are more susceptible to apoptosis in vitro, which is 
associated with a 4-fold increase of plaque necrotic core in vivo. In addition, 
chimeric Pla2g10(-/-) mice show exaggerated T lymphocyte (Th)1 immune response, 
associated with enhanced T-cell infiltration in atherosclerotic plaques. 
Interestingly, overexpression of human PLA2G10 in murine bone marrow cells leads 
to significant reduction of Th1 response and to 50% reduction of lesion size.
CONCLUSIONS: PLA2G10 expression in bone marrow cells controls a proatherogenic 
Th1 response and limits the development of atherosclerosis. The results may 
provide an explanation for the recently reported inefficacy of A-002 
(varespladib) to treat patients with coronary artery disease. Indeed, A-002 is a 
nonselective sPLA2 inhibitor that inhibits both proatherogenic (groups IIA and 
V) and antiatherogenic (group X) sPLA2s. Our results suggest that selective 
targeting of individual sPLA2 enzymes may be a better strategy to treat 
cardiovascular diseases.