A novel antioxidant Mito-Tempol inhibits ox-LDL-induced foam cell formation through restoration of autophagy flux.

A bulk of cholesteryl esters accumulation in macrophage foam cells drives the occurrence and development of atherosclerosis. Evidence now shows that autophagy plays key roles in the degradation of intracellular lipid droplets via autolysosome, and also in the release of intracellular lipids via cholesterol efflux. In this study, we identified that a mitochondria-targeted antioxidant, Mito-Tempol, has protective effects against cholesteryl esters accumulation by activating autophagy. Mito-Tempol was shown to ameliorate the lipid burden for atherosclerosis, both in vitro and in vivo. In the established in vitro foam cell formation system using oxidized low-density lipoprotein (ox-LDL)-loaded THP-1 macrophages, Mito-Tempol prevented intracellular oxidative stress and attenuated lipid accumulation. Mito-Tempol rescued ox-LDL-impaired autophagic flux, thereby facilitating autophagy-mediated lipid degradation in THP-1 macrophages. Meanwhile, Mito-Tempol also increased the efflux of cholesterol via autophagy-dependent ABCA1 and ABCG1 up-regulation. The classical autophagy pathway of mTOR may be one of the effector for the autophagy restoration of Mito-Tempol. Our findings give the first insight that cardiovascular system disease may benefits more from the treatment of Mito-Tempol for its impact of reversing atherosclerosis via autophagy.