Group X secreted phospholipase A2 limits the development of atherosclerosis in LDL receptor-null mice.
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.


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.
Inserm U970, Paris Cardiovascular Research Center, Université René Descartes, Paris, France.
Hafid
H
Ait-Oufella
Olivier
O
Herbin
Charlotte
C
Lahoute
Christelle
C
Coatrieux
Xavier
X
Loyer
Jeremie
J
Joffre
Ludivine
L
Laurans
Bhama
B
Ramkhelawon
Olivier
O
Blanc-Brude
Sonia
S
Karabina
Christophe A
CA
Girard
Christine
C
Payré
Kei
K
Yamamoto
Christoph J
CJ
Binder
Makoto
M
Murakami
Alain
A
Tedgui
Gérard
G
Lambeau
Ziad
Z
Mallat
D056704:Adaptive Immunity; D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D017209:Apoptosis; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D054509:Group X Phospholipases A2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009336:Necrosis; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology; D013997:Time Factors
D011973:Receptors, LDL; D054509:Group X Phospholipases A2; C516365:PLA2G10 protein, human; C516366:Pla2g10 protein, mouse