Effects of Ethyl Pyruvate in Preventing the Development of Diet-induced Atherosclerosis by Blocking the HMGB1 Expression in ApoE-Deficient Mice

J Cardiovasc Pharmacol. 2016 Apr;67(4):299-304. doi: 10.1097/FJC.0000000000000353.

Abstract

Ethyl pyruvate (EP) is a lipid derivative of pyruvate and known as an anti-inflammatory agent effective to inhibit many diseases in experimental models. To test the hypothesis that Ethyl pyruvate might prevent atherosclerosis development by blocking the high-mobility group box-1 (HMGB1) expression, 8-week-old ApoE-deficient (ApoE-/-) mice were fed a high-fat diet and treated with EP (50 mg/Kg) or Physiological saline for 12 weeks. THP-1 cells were then differentiated into macrophages by treated with Phorbol-12-myristate-13-acetate (PMA, 100 ng/mL) and incubated with oxidized low-density lipoprotein (oxLDL) only or added with EP (5 mM) for 24 hour. In ApoE-/- mice, EP markedly reduced aortic sinus atherosclerosis lesions with no influence to serum lipid levels. Inhibited HMGB1 expression, decreased macrophages content and reduced Toll-like-receptor2 (TLR2), TLR4, monocyte chemotactic protein 1 (MCP-1) and Tumor Necrosis Factor α (TNF-α) mRNA levels were also observed at the same time. In vitro, EP decreased oxLDL uptake in macrophages and inhibited HMGB1 expression induced by oxLDL. In conclusion, our study indicated that EP was an effective agent against the development of diet-induced atherosclerosis in ApoE-deficient mice by way of blocking the HMGB1 expression.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Apolipoproteins E / genetics*
  • Atherosclerosis / etiology
  • Atherosclerosis / prevention & control*
  • Diet, High-Fat
  • Gene Expression Regulation / drug effects
  • HMGB1 Protein / genetics*
  • Lipids / blood
  • Lipoproteins, LDL / administration & dosage
  • Lipoproteins, LDL / metabolism
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Pyruvates / pharmacology*
  • Tetradecanoylphorbol Acetate / pharmacology

Substances

  • Anti-Inflammatory Agents
  • Apolipoproteins E
  • HMGB1 Protein
  • Lipids
  • Lipoproteins, LDL
  • Pyruvates
  • oxidized low density lipoprotein
  • ethyl pyruvate
  • Tetradecanoylphorbol Acetate