Novel PPARα selective agonist K-877 suppresses pro-inflammatory macrophage activation and arterial lesion formation

Background Pro-inflammatory macrophage activation promotes vascular diseases. Using the novel selective agonist K-877, we tested the hypothesis that activation of the nuclear receptor PPARα exerts anti-inflammatory effects in... [ view full abstract ]

Background Pro-inflammatory macrophage activation promotes vascular diseases. Using the novel selective agonist K-877, we tested the hypothesis that activation of the nuclear receptor PPARα exerts anti-inflammatory effects in macrophages and attenuates arterial disease. Methods and Results Network prediction analysis, using random work methodology based on functional databases (e.g., GWAS, OMIM), revealed the close relationship between the PPARα gene network and the coronary artery disease module (p<0.001). In human macrophage cell line THP-1, silencing PPARα induced expression of TNFα and IL-1β, markers of a pro-inflammatory macrophage phenotype, indicating the anti-inflammatory role of PPARα. In mouse and human macrophages, K-877 suppressed IFNγ or LPS-induced expression of pro-inflammatory molecules (e.g., TNFα, IL-1β, iNOS, IL-6) at lower concentrations than the conventional PPARα agonist fenofibric acid. K-877 affected the recruitment of co-factors (e.g., PGC-1α/β, SRC) to PPARα at lower concentrations (< 1/1000-7000) than those of fenofibric acid. K-877 rescued IFNγ-induced suppression of NcoR1 and NcoR2 (SMRT), co-repressors of pro-inflammatory cytokines. In addition, K-877 suppressed other pro-inflammatory mechanisms, including IFNγ−induced endothelial cell activation, as gauged by decreased expression of VCAM-1 and MCP-1. In vivo administration of K-877 in Ldlr-/- mice suppressed hepatic expression of the pro-inflammatory apoprotein apoC-III (p<0.01, n=7-8/group, Figure A), which has been linked with coronary risk. To further examine its effects on arterial disease, we administered K-877 in LDL receptor deficient mice. K-877 reduced macrophage accumulation in femoral arteries 28 days after mechanical injury (p<0.05, n=5-7/group, Figure B). Conclusion Anti-inflammatory properties of K-877 may attenuate atherosclerotic vascular diseases and other inflammatory disorders.