| First Author | Ait-Oufella H | Year | 2013 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 33 |
| Issue | 3 | Pages | 466-73 |
| PubMed ID | 23349189 | Mgi Jnum | J:216884 |
| Mgi Id | MGI:5609901 | Doi | 10.1161/ATVBAHA.112.300309 |
| Citation | Ait-Oufella H, et al. (2013) Group X secreted phospholipase A2 limits the development of atherosclerosis in LDL receptor-null mice. Arterioscler Thromb Vasc Biol 33(3):466-73 |
| abstractText | 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. |
