Abstract 510: Gene Set Enrichment Analysis of the Dual PPAR-α/γ Agonists Aleglitazar and Muraglitazar Reveals Distinct Metabolic Signatures in Human Cardiomyocytes
Dual-acting agonists of the peroxisome proliferator-activated receptors α and γ (PPAR-α/γ) have been pursued to reduce cardiovascular risk in type 2 diabetes. Although core PPAR signaling appears conserved, compound-specific on- and off-target effects contribute to profiles of specific molecules. Here, we used gene set enrichment analysis (GSEA) to compare the effect of dual PPAR-α/γ agonists aleglitazar (Ale) and muraglitazar (Mura).
Primary human cardiomyocytes were incubated with non-cytotoxic concentrations of Ale or Mura (both 1 nM to 25 μM). Whole-genome expression studies were carried out using Illumina microarrays. Principal Component Analysis, hierarchical clustering and GSEA using the publicly available Pathway Commons database identified multiple signaling and metabolic networks significantly regulated by both compounds. Effects of Mura at the higher concentrations substantially diverged from both Ale and low concentrations of Mura, suggesting potential off-target effects. Within the Pathways Commons collection analyzed, four networks were significantly differentially affected by 25 μM Mura versus the other treatments.
Nuclear Factor Y, which recognizes CCAAT elements, was identified as a common signature of Mura-specific effects on the cholesterol biosynthesis pathway (seven genes, p = 0.003 for enrichment).
The divergent effects of Ale and Mura on metabolic, energy regulation and interferon signaling pathways may contribute to their unique biological profile.
- © 2012 by American Heart Association, Inc.