The Basic Science of Lp-PLA2

Lipoprotein-associated phospholipase A2 (Lp-PLA2)

  • 50kDa, Ca-insensitive lipase
  • Produced predominantly by macrophages
  • An enzyme that resides mainly on LDL in human plasma
  • Distinct from secretory phospholipase A2 (sPLA2)
  • Levels are not affected by acute systemic inflammatory conditions
  • Intra-individual variability is similar to other lipid parameters, such as LDL-C and TC

Lp-PLA2 is Related to Atherosclerosis

  • Elevated plasma levels correlate with CHD and ischemic stroke risk
  • Highly up-regulated in atherosclerotic plaques
  • The enzyme Lp-PLA2 is implicated in formation of inflamed, rupture-prone plaque
  • Responsible for generating two pro-inflammatory mediators during LDL oxidation
    • lysophosphatidylcholine (Lyso-PC)
    • oxidized fatty acid (OxFA)
  • In pre-clinical animal studies, inhibition of the enzyme attenuates the inflammatory process and slows atherosclerotic disease progression

Pro-atherogenic Activities of Lysophosphatidylcholine (Lyso-PC)

  • Impairment of endothelium dependent relaxation
  • Induces expression of vascular adhesion molecules
  • Chemoattractant for inflammatory cells
  • Up-regulation of Cytokines and CD 40 Ligand
  • Stimulation of macrophage proliferation
  • Cytotoxic to vascular smooth muscle cells

Lp-PLA2 is a Potential Therapeutic Target for Anti-Atherosclerotic Treatments

  • GlaxoSmithKline (GSK) is currently developing small molecule inhibitors as potential treatments for atherosclerotic disease
  • Currently available medications that are known to reduce cardiovascular events, such as statins and fibrates, are also known to reduce Lp-PLA2 levels

Lp-PLA2 and

Vulnerable Plaque

The thin fibrous cap may burst and form a thrombotic clot that can lead to a stroke or coronary event. (Click to enlarge)


 

Click below to view a short animation that illustrates how Lp-PLA2 contributes to the formation of vulnerable plaque, which can cause CHD or stroke.