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

Free Radic Biol Med. 2018 Dec:129:463-472. doi: 10.1016/j.freeradbiomed.2018.10.412. Epub 2018 Oct 12.


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.

Keywords: Atherosclerosis; Autophagy; Foam cells; Macrophage; Mito-Tempol; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / agonists
  • ATP Binding Cassette Transporter 1 / genetics
  • ATP Binding Cassette Transporter 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 1 / agonists
  • ATP Binding Cassette Transporter, Subfamily G, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 1 / metabolism
  • Animals
  • Antioxidants / pharmacology*
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Autophagy / drug effects
  • Autophagy / genetics*
  • Cell Differentiation / drug effects
  • Cholesterol Esters / metabolism
  • Cyclic N-Oxides / pharmacology*
  • Foam Cells / drug effects
  • Foam Cells / metabolism
  • Foam Cells / pathology
  • Gene Expression Regulation
  • Humans
  • Hypertension / drug therapy*
  • Hypertension / genetics
  • Hypertension / metabolism
  • Hypertension / pathology
  • Lipoproteins, LDL / pharmacology
  • Male
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Oxidative Stress
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Signal Transduction
  • Spin Labels
  • THP-1 Cells
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Tetradecanoylphorbol Acetate / pharmacology


  • ABCA1 protein, human
  • ABCG1 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • Antioxidants
  • Cholesterol Esters
  • Cyclic N-Oxides
  • Lipoproteins, LDL
  • Spin Labels
  • oxidized low density lipoprotein
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Tetradecanoylphorbol Acetate
  • tempol