Abstract 16180: K-877, A Novel PPAR-alpha Selective Agonist, Suppresses Macrophage Activation and Arterial Lesion Formation
Background: Macrophage activation contributes to the development of atherosclerotic vascular diseases and metabolic disorders. An emerging concept suggests that a microenvironment with dominance of pro-inflammatory (so-called M1) macrophages mediate cardiometabolic diseases while M2 macrophages mitigate inflammation. To test the hypothesis that the nuclear receptor PPARα pathway plays an anti-inflammatory role through suppression of the M1 macrophage polarization and induction of M2, we used the novel and potent PPARα selective agonist K-877.
Methods and Results: In mouse and human macrophage cell lines RAW264.7 and THP-1 and mouse and human primary macrophages, we induced M1 macrophage polarization with IFN-γ or LPS. K-877 suppressed the induction of mRNA and protein levels of TNF-α, iNOS, IL-1β and IL-6, pro-inflammatory molecules typical of M1 macrophages. In contrast, K-877 induced the anti-inflammatory M2 marker IL-10. In human macrophages, a clinically achievable concentration of K-877 (100 nM) exerted such anti-inflammatory effects, while other PPARα agonists gemfibrozil and fenofibric acid required higher concentrations (> 10 μM) (Figure A). Silencing of PPARα with siRNA attenuated suppression of the M1 genes, indicating that this nuclear receptor indeed mediates anti-inflammatory effects of K-877. K-877 recruited co-activators for PPARα gene expression (e.g., PGC-1α/β, SRC1, NCOR) at 1000-fold lower concentrations than fenofibric acid. Global proteomic and cluster analyses demonstrated that, while IFN-γ induced 368 proteins in THP-1 cells, K-877 abrogated induction of 305 of these molecules. In vivo K-877 administration reduced lesion development in mouse femoral arteries after mechanical injury (Figure B).
Conclusion: These results support a pivotal anti-inflammatory role for PPARα agonism. The potent PPARα activator K-877 merits evaluation as a therapy for atherosclerotic vascular diseases and other inflammatory disorders.
- © 2013 by American Heart Association, Inc.