Antimitogenic effects of HDL and APOE mediated by Cox-2-dependent IP activation

J Clin Invest. 2004 Feb;113(4):609-18. doi: 10.1172/JCI19097.

Abstract

HDL and its associated apo, APOE, inhibit S-phase entry of murine aortic smooth muscle cells. We report here that the antimitogenic effect of APOE maps to the N-terminal receptor-binding domain, that APOE and its N-terminal domain inhibit activation of the cyclin A promoter, and that these effects involve both pocket protein-dependent and independent pathways. These antimitogenic effects closely resemble those seen in response to activation of the prostacyclin receptor IP. Indeed, we found that HDL and APOE suppress aortic smooth muscle cell cycle progression by stimulating Cox-2 expression, leading to prostacyclin synthesis and an IP-dependent inhibition of the cyclin A gene. Similar results were detected in human aortic smooth muscle cells and in vivo using mice overexpressing APOE. Our results identify the Cox-2 gene as a target of APOE signaling, link HDL and APOE to IP action, and describe a potential new basis for the cardioprotective effect of HDL and APOE.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aorta / anatomy & histology
  • Apolipoproteins E / metabolism*
  • Cells, Cultured
  • Cyclin A / genetics
  • Cyclin A / metabolism
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / metabolism
  • Gene Expression Regulation
  • Humans
  • Isoenzymes / metabolism*
  • Lipoproteins, HDL / metabolism*
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth / cytology
  • Muscle, Smooth / metabolism
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / metabolism*
  • Promoter Regions, Genetic
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Rats
  • Receptors, Epoprostenol
  • Receptors, Prostaglandin / genetics
  • Receptors, Prostaglandin / metabolism*
  • S Phase / physiology*
  • Sulfonamides / metabolism

Substances

  • Apolipoproteins E
  • Cyclin A
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Lipoproteins, HDL
  • Membrane Proteins
  • PTGIR protein, human
  • Ptgir protein, mouse
  • Ptgir protein, rat
  • Receptors, Epoprostenol
  • Receptors, Prostaglandin
  • Sulfonamides
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • nimesulide