Paeonol suppresses lipid accumulation in macrophages via upregulation of the ATP-binding cassette transporter A1 and downregulation of the cluster of differentiation 36

Abstract

Paeonol, a potent antioxidant isolated from cortex moutan, possesses athero-protective activity, yet the detailed mechanisms are not fully investigated. This study was conducted to explore the role of paeonol and its underlying mechanisms in RA W264.7 macrophages and apolipoprotein E- deficient (ApoE-/-) mice. Paeonol treatment significantly attenuated intracellular lipid accumulation in macrophages, which may be the result of decreased oxidized low-density lipoprotein (ox-L DL) uptake and increased cholesterol efflux. Additionally, paeonol markedly inhibited the mRNA and protein expression of the cluster of differentiation 36 (CD36) by decreasing nuclear translocation of c-J un [a subunit of activator protein-1 (AP-1)]. Moreover, paeonol upregulated the protein stability of AT P-binding cassette transporter A1 (ABCA 1) by inhibiting calpain activity, while ABCA 1 mRNA expression was not altered. Furthermore, small hairpin RNA (shRNA ) targeting haem oxygenase-1 (HO- 1) inhibited the paeonol-mediated beneficial effects on the expression of c-J un, CD36, ABCA 1, calpain activity and lipid accumulation in macrophages. Accordingly, paeonol retarded the progress of atherosclerosis in ApoE-/- mice and modulated the expression of CD36 and ABCA 1 in aortas similarly to that observed in macrophages. These results indicate that paeonol provides protective effects on foam cell formation by a novel HO- 1-dependent mediation of cholesterol efflux and lipid accumulation in macrophages.