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

Arterioscler Thromb Vasc Biol. 2013 Mar;33(3):466-73. doi: 10.1161/ATVBAHA.112.300309. Epub 2013 Jan 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Animals
  • Aorta, Thoracic / enzymology*
  • Aorta, Thoracic / immunology
  • Aorta, Thoracic / pathology
  • Aortic Diseases / enzymology
  • Aortic Diseases / genetics
  • Aortic Diseases / immunology
  • Aortic Diseases / pathology
  • Aortic Diseases / prevention & control*
  • Apoptosis
  • Atherosclerosis / enzymology
  • Atherosclerosis / genetics
  • Atherosclerosis / immunology
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • Bone Marrow Transplantation
  • Cells, Cultured
  • Coculture Techniques
  • Disease Models, Animal
  • Group X Phospholipases A2 / deficiency
  • Group X Phospholipases A2 / genetics
  • Group X Phospholipases A2 / metabolism*
  • Humans
  • Macrophages / immunology
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Necrosis
  • Plaque, Atherosclerotic
  • Receptors, LDL / deficiency*
  • Receptors, LDL / genetics
  • Th1 Cells / immunology
  • Time Factors


  • Receptors, LDL
  • Group X Phospholipases A2
  • PLA2G10 protein, human
  • Pla2g10 protein, mouse