Open AccessAtherosclerotic Plaque Inflammation Varies Between Vascular Sites and Correlates With Response to Inhibition of Lipoprotein‐Associated Phospholipase A 2
Author(s) -
Fenning Robert S.,
Burgert Mark E.,
Hamamdzic Damir,
Peyster Eliot G.,
Mohler Emile R.,
Kangovi Shreya,
Jucker Beat M.,
Lenhard Stephen C.,
Macphee Colin H.,
Wilensky Robert L.
Publication year - 2015
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.114.001477
Subject(s) - medicine , inflammation , vulnerable plaque , lipoprotein associated phospholipase a2 , diabetes mellitus , macrophage , pathology , gastroenterology , lipoprotein , endocrinology , cholesterol , in vitro , biochemistry , chemistry
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 ( COR s) and distal abdominal aortas ( AA s). 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 COR s and AA s of 17 DM / HC pigs. To assess the role of lipoprotein‐associated phospholipase A 2 (Lp‐ PLA 2 ) in plaque development, 20 DM / HC pigs were treated with the Lp‐ PLA 2 inhibitor darapladib and compared with the 17 DM / HC untreated pigs. DM / HC caused site‐specific differences in plaque severity. In the AA s, 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 COR s. DM / HC caused differential expression of 8 of 87 atherosclerotic genes studied, including 3 important in inflammation with higher expression in the COR s. Darapladib‐induced attenuation of normalized plaque area was site‐specific, as COR s responded 2.9‐fold more than AA s ( P =0.045). Conclusions While plaque severity was worse in the AA s, inflammatory genes and inflammatory pathways that use Lp‐ PLA 2 were more important in the COR s. Our results suggest fundamental differences in inflammation between vascular sites, an important finding for the development of novel anti‐inflammatory therapeutics.