Macrophage-specific expression of group IIA sPLA2 results in accelerated atherogenesis by increasing oxidative stress

J Lipid Res. 2005 Aug;46(8):1604-14. doi: 10.1194/jlr.M400469-JLR200. Epub 2005 May 16.


Group IIA secretory phospholipase A2 (sPLA2) is an acute-phase protein mediating decreased plasma HDL cholesterol and increased atherosclerosis. This study investigated the impact of macrophage-specific sPLA2 overexpression on lipoprotein metabolism and atherogenesis. Macrophages from sPLA2 transgenic mice have 2.5 times increased rates of LDL oxidation (thiobarbituric acid-reactive substances formation) in vitro (59 +/- 5 vs. 24 +/- 4 nmol malondialdehyde/mg protein; P < 0.001) dependent on functional 12/15-lipoxygenase (12/15-LO). Low density lipoprotein receptor-deficient (LDLR-/-) mice were transplanted with bone marrow from either sPLA2 transgenic mice (sPLA2--> LDLR-/-; n = 19) or wild-type C57BL/6 littermates (C57 BL/6-->LDLR-/-; n = 19) and maintained for 8 weeks on chow and then for 9 weeks on a Western-type diet. Plasma sPLA2 activity and plasma lipoprotein profiles were not significantly different between sPLA2-->LDLR-/- and C57BL/6-->LDLR-/- mice. Aortic root atherosclerosis was increased by 57% in sPLA2-->LDLR-/- mice compared with C57BL/6-->LDLR-/- controls (P < 0.05). Foam cell formation in vitro and in vivo was increased significantly. Urinary, plasma, and aortic levels of the isoprostane 8,12-iso-iPF2alpha-VI and aortic levels of 12/15-LO reaction products were each significantly higher (P < 0.001) in sPLA2-->LDLR-/- compared with C57BL/6-->LDLR-/- mice, indicating significantly increased in vivo oxidative stress in sPLA2--> LDLR-/-. These data demonstrate that macrophage-specific overexpression of human sPLA2 increases atherogenesis by directly modulating foam cell formation and in vivo oxidative stress without any effect on systemic sPLA2 activity and lipoprotein metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Atherosclerosis / etiology*
  • Atherosclerosis / metabolism
  • Bone Marrow Transplantation
  • Foam Cells / pathology
  • Group II Phospholipases A2
  • Humans
  • Lipoproteins / metabolism
  • Macrophages / chemistry
  • Macrophages / metabolism*
  • Mice
  • Mice, Transgenic
  • Oxidative Stress / genetics*
  • Phospholipases A / genetics*
  • Phospholipases A / metabolism
  • Phospholipases A2
  • Receptors, LDL / genetics


  • Lipoproteins
  • Receptors, LDL
  • Phospholipases A
  • Group II Phospholipases A2
  • Phospholipases A2