Atherosclerotic plaque inflammation varies between vascular sites and correlates with response to inhibition of lipoprotein-associated phospholipase A2

J Am Heart Assoc. 2015 Feb 11;4(2):e001477. doi: 10.1161/JAHA.114.001477.


Background: Despite systemic exposure to risk factors, the circulatory system develops varying patterns of atherosclerosis for unclear reasons. In a porcine model, we investigated the relationship between site-specific lesion development and inflammatory pathways involved in the coronary arteries (CORs) and distal abdominal aortas (AAs).

Methods and results: Diabetes mellitus (DM) and hypercholesterolemia (HC) were induced in 37 pigs with 3 healthy controls. Site-specific plaque development was studied by comparing plaque severity, macrophage infiltration, and inflammatory gene expression between CORs and AAs of 17 DM/HC pigs. To assess the role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in plaque development, 20 DM/HC pigs were treated with the Lp-PLA2 inhibitor darapladib and compared with the 17 DM/HC untreated pigs. DM/HC caused site-specific differences in plaque severity. In the AAs, normalized plaque area was 4.4-fold higher (P<0.001) and there were more fibroatheromas (9 of the 17 animals had a fibroatheroma in the AA and not the COR, P=0.004), while normalized macrophage staining area was 1.5-fold higher (P=0.011) compared with CORs. DM/HC caused differential expression of 8 of 87 atherosclerotic genes studied, including 3 important in inflammation with higher expression in the CORs. Darapladib-induced attenuation of normalized plaque area was site-specific, as CORs responded 2.9-fold more than AAs (P=0.045).

Conclusions: While plaque severity was worse in the AAs, inflammatory genes and inflammatory pathways that use Lp-PLA2 were more important in the CORs. Our results suggest fundamental differences in inflammation between vascular sites, an important finding for the development of novel anti-inflammatory therapeutics.

Keywords: arteriosclerosis; coronary disease; darapladib; inflammation; lipoprotein‐associated phospholipase A2; peripheral vascular disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / antagonists & inhibitors*
  • Animals
  • Aorta, Abdominal / immunology
  • Aorta, Abdominal / pathology*
  • Atherosclerosis / metabolism*
  • Benzaldehydes / pharmacology
  • Coronary Vessels / immunology
  • Coronary Vessels / pathology*
  • Diabetes Mellitus / immunology
  • Diabetes Mellitus / pathology
  • Disease Models, Animal
  • Gene Expression / drug effects
  • Hypercholesterolemia / immunology
  • Hypercholesterolemia / pathology
  • Inflammation / metabolism*
  • Macrophages / immunology
  • Male
  • Oximes / pharmacology
  • Phospholipase A2 Inhibitors / pharmacology
  • Plaque, Atherosclerotic / metabolism
  • Plaque, Atherosclerotic / pathology*
  • Swine


  • Benzaldehydes
  • Oximes
  • Phospholipase A2 Inhibitors
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • darapladib