Group IVA phospholipase A2-associated production of MMP-9 in macrophages and formation of atherosclerotic lesions

Biol Pharm Bull. 2008 Mar;31(3):363-8. doi: 10.1248/bpb.31.363.


Matrix metalloproteinase-9 (MMP-9) is involved in atherogenesis, and the production of MMP-9 in macrophages is considered to be mediated by the arachidonic acid cascade. The present study examined the possible involvement of group IVA phospholipase A2 (IVA-PLA2), a key enzyme in the arachidonic acid cascade, in the production of MMP-9 induced by oxidized low-density lipoprotein (oxLDL) in macrophages and high-fat diet-induced formation of atherosclerotic lesions using IVA-PLA2-deficient mice (C57BL/6 background). In wild-type mouse peritoneal macrophages, oxLDL induced an increase in MMP-9 in the culture medium. The oxLDL-promoted production of MMP-9 was markedly reduced in IVA-PLA2-deficient macrophages compared to wild-type macrophages. Feeding of wild-type mice with a high-fat diet caused the formation of early atherosclerotic lesions in the aortic root with increases in MMP-9 and macrophages in the lesions and with higher serum levels of total cholesterol. Such lesions were apparently less severe in IVA-PLA2-deficient mice fed a high-fat diet, despite higher total cholesterol levels. Under the conditions, a high-fat diet reduced the serum levels of high-density lipoprotein-cholesterol (HDL-C) in wild-type mice. However, IVA-PLA2-deficient mice fed a high-fat diet were protected against the decrease in HDL-C levels. The present results suggest that IVA-PLA2 is involved in the oxLDL-induced production of MMP-9 in macrophages and the high-fat diet-induced formation of early atherosclerotic lesions. The protection against the lesions in IVA-PLA2-deficient mice may be ascribable, in part, to the impaired production of MMP-9 and/or the maintained levels of HDL-C.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / enzymology
  • Aorta / pathology
  • Arachidonic Acid / metabolism
  • Atherosclerosis / enzymology*
  • Atherosclerosis / etiology
  • Atherosclerosis / pathology
  • Diet, Atherogenic*
  • Dietary Fats / administration & dosage
  • Female
  • Group IV Phospholipases A2 / deficiency
  • Group IV Phospholipases A2 / genetics
  • Group IV Phospholipases A2 / metabolism*
  • Humans
  • Lipids / blood
  • Lipoproteins, LDL / pharmacology
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / enzymology*
  • Macrophages, Peritoneal / metabolism
  • Matrix Metalloproteinase 9 / biosynthesis*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout


  • Dietary Fats
  • Lipids
  • Lipoproteins, LDL
  • oxidized low density lipoprotein
  • Arachidonic Acid
  • Group IV Phospholipases A2
  • Matrix Metalloproteinase 9