title: Atherosclerotic plaque inflammation varies between vascular sites and correlates with response to inhibition of lipoprotein-associated phospholipase A2.
abstract: 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).
  
  
  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.
authors: Hospital of the University of Pennsylvania, Philadelphia, PA (R.S.F., D.H., E.G.P., E.R.M., S.K., R.L.W.).
authors: Robert S
authors: RS
authors: Fenning
authors: GlaxoSmithKline, King of Prussia, PA (M.E.B., B.M.J., S.C.L., C.H.M.).
authors: Mark E
authors: ME
authors: Burgert
authors: Hospital of the University of Pennsylvania, Philadelphia, PA (R.S.F., D.H., E.G.P., E.R.M., S.K., R.L.W.).
authors: Damir
authors: D
authors: Hamamdzic
authors: Hospital of the University of Pennsylvania, Philadelphia, PA (R.S.F., D.H., E.G.P., E.R.M., S.K., R.L.W.).
authors: Eliot G
authors: EG
authors: Peyster
authors: Hospital of the University of Pennsylvania, Philadelphia, PA (R.S.F., D.H., E.G.P., E.R.M., S.K., R.L.W.).
authors: Emile R
authors: ER
authors: Mohler
authors: Hospital of the University of Pennsylvania, Philadelphia, PA (R.S.F., D.H., E.G.P., E.R.M., S.K., R.L.W.).
authors: Shreya
authors: S
authors: Kangovi
authors: GlaxoSmithKline, King of Prussia, PA (M.E.B., B.M.J., S.C.L., C.H.M.).
authors: Beat M
authors: BM
authors: Jucker
authors: GlaxoSmithKline, King of Prussia, PA (M.E.B., B.M.J., S.C.L., C.H.M.).
authors: Stephen C
authors: SC
authors: Lenhard
authors: GlaxoSmithKline, King of Prussia, PA (M.E.B., B.M.J., S.C.L., C.H.M.).
authors: Colin H
authors: CH
authors: Macphee
authors: Hospital of the University of Pennsylvania, Philadelphia, PA (R.S.F., D.H., E.G.P., E.R.M., S.K., R.L.W.).
authors: Robert L
authors: RL
authors: Wilensky
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors*; D000818:Animals; D001012:Aorta, Abdominal / Q000276:immunology / Q000473:pathology*; D050197:Atherosclerosis / Q000378:metabolism*; D001547:Benzaldehydes / Q000494:pharmacology; D003331:Coronary Vessels / Q000276:immunology / Q000473:pathology*; D003920:Diabetes Mellitus / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D006937:Hypercholesterolemia / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D008297:Male; D010091:Oximes / Q000494:pharmacology; D064801:Phospholipase A2 Inhibitors / Q000494:pharmacology; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology*; D013552:Swine; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes; D010091:Oximes; D064801:Phospholipase A2 Inhibitors; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
keywords: arteriosclerosis; coronary disease; darapladib; inflammation; lipoprotein‐associated phospholipase A2; peripheral vascular disease