Abstract 12287: Atherosclerotic Plaque Development Differs between Vascular Sites with Unique Phenotypic and Gene Expression Profiles
It is unclear whether the same inflammatory pathways play a role in coronary and peripheral atherosclerosis. Using a diabetic (DM), hypercholesterolemic (HC) porcine model, we hypothesized that coronary (COR) and abdominal aortic/proximal iliac (AA) lesions would vary by phenotype and gene expression profiles. One month after DM/HC induction, pigs were randomized to receive either placebo (n=17) or darapladib (n=20), an inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2). After 28 weeks tissues were harvested. Compared to CORs, AAs had more extensive disease with higher risk features (Table 1). In AAs, lesion area correlated with cholesterol (p=0.016) and glucose (p=0.006) levels while in CORs there was no correlation (p=0.579, p=0.842 respectively). As previously published, treatment with darapladib reduced lesion size, instability, and macrophage content in the CORs. In contrast (Table 2), treatment did not affect AA lesions. Darapladib had differential effects on gene expression in AAs and CORs. In CORs, darapladib decreased the expression of 24 of 87 genes studied including macrophage and T cell genes: cathepsin S, CD68, CXCR3, CCR2, and MCP-1. In AAs, darapladib affected 9 different genes. While there was a general trend towards inhibition of inflammation for the AA, it was not as pronounced as observed for the CORs. In conclusion, inflammatory pathways utilizing Lp-PLA2 are important for disease progression and instability in the CORs but not the AAs. This has important implications not only for assumptions regarding the universality of atherosclerosis, but also for the development of targeted anti-inflammatory drugs for treatment of atherosclerosis.
- © 2012 by American Heart Association, Inc.