High-fat diet increases and the polyphenol, S17834, decreases acetylation of the sirtuin-1-dependent lysine-382 on p53 and apoptotic signaling in atherosclerotic lesion-prone aortic endothelium of normal mice

J Cardiovasc Pharmacol. 2011 Sep;58(3):263-71. doi: 10.1097/FJC.0b013e3182239eb7.


Our purpose was to determine if high-fat diet and treatment with a polyphenol regulate the acetylation of lysine-382 of p53, the site regulated by sirtuin-1, and apoptosis in the endothelium of the atherosclerotic lesion-prone mouse aortic arch. In cultured endothelial cells, 2 atherogenic stimuli, hydrogen peroxide and tumor necrosis factor-α, increased the acetylation of p53 lysine-382, and caspase-3 cleavage, an indicator of apoptotic signaling. The polyphenol, S17834, significantly prevented these changes. In low-density lipoprotein receptor-deficient mice, a high-fat diet increased, and treatment with S17834 attenuated early atherosclerotic lesions on the lesser curvature of the aortic arch. In wild-type C57BL6 mice fed the same diet, no atherosclerotic lesions were observed in this lesion-prone area, but p53 acetylation and caspase-3 cleavage increased in the endothelium. In high-fat fed mice, S17834 increased sirtuin-1 protein in the lesion-prone endothelium and prevented both the increase in p53 acetylation and caspase-3 cleavage without affecting blood lipids. These results indicate that high-fat diet increases and S17834 decreases the acetylation of p53 in lesion-prone aortic endothelial cells of normal mice independently of blood lipids, suggesting that the polyphenol may regulate endothelial cell p53 acetylation and apoptosis via local actions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Aorta, Thoracic / metabolism
  • Aorta, Thoracic / pathology
  • Apoptosis
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / enzymology
  • Atherosclerosis / pathology
  • Atherosclerosis / physiopathology
  • Benzopyrans / metabolism
  • Benzopyrans / pharmacokinetics
  • Benzopyrans / pharmacology*
  • Caspase 3 / metabolism
  • Cells, Cultured
  • Diet, High-Fat*
  • Disease Models, Animal
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism
  • Hypolipidemic Agents / metabolism
  • Hypolipidemic Agents / pharmacology*
  • Lipids / blood
  • Lysine / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Polyphenols / metabolism
  • Polyphenols / pharmacokinetics
  • Polyphenols / pharmacology*
  • Signal Transduction
  • Sirtuin 1 / metabolism*
  • Superoxides / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / metabolism*


  • 6,8-diallyl 5,7-dihydroxy 2-(2-allyl 3-hydroxy 4-methoxyphenyl)1-H benzo(b)pyran-4-one
  • Benzopyrans
  • Hypolipidemic Agents
  • Lipids
  • Polyphenols
  • Tumor Suppressor Protein p53
  • Superoxides
  • Caspase 3
  • Sirtuin 1
  • Lysine