Simvastatin suppresses coronary artery endothelial tube formation by disrupting Ras/Raf/ERK signaling

Atherosclerosis. 2004 Aug;175(2):235-43. doi: 10.1016/j.atherosclerosis.2004.04.017.


Since we recently demonstrated that high-density lipoprotein induced human coronary artery endothelial cell (HCEC) tube formation through Ras/Raf/ERK (extracellular-signal-regulated kinase) activation [Arterioscler. Thromb. Vasc. Biol. 23 (2003) 802], it is possible that lipid-lowering agents such as statins, which reduce the prenylation of Ras, could decrease such tube formation. Therefore, we investigated whether this event occurs through inhibition of the Ras/Raf/ERK pathway. We developed an in vitro model of EC tube formation on a matrix gel. Simvastatin inhibited serum-induced endothelial tube formation after 18 h. The inhibition of ERK activity suppressed serum-induced tube formation. Farnesylpyrophosphate (Fpp), which translocates Ras from the cytoplasm to the cell membrane, rescued this inhibition. In addition, farnesyltransferase I inhibitor, which inhibits Ras farnesylation, and dominant-negative Ras (N17) also inhibited serum-induced tube formation. Although Fpp activated Ras assessed by a Ras pull-down assay and phospho(p)-ERK1/2, Fpp-induced p-ERK1/2 activation was not inhibited by simvastatin. In conclusion, simvastatin-induced Ras/Raf/ERK inactivation is a potent signal in the anti-angiogenic phenotype of HCECs. Fpp counteracted simvastatin-induced Ras/Raf/ERK inactivation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Culture Techniques
  • Collagen
  • Coronary Vessels / cytology
  • Coronary Vessels / drug effects
  • Drug Combinations
  • Endothelial Cells / drug effects*
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Laminin
  • MAP Kinase Signaling System / drug effects*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Neovascularization, Physiologic / drug effects*
  • Protein Prenylation / drug effects
  • Proteoglycans
  • Simvastatin / pharmacology*


  • Drug Combinations
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Laminin
  • Proteoglycans
  • matrigel
  • Collagen
  • Simvastatin
  • Mitogen-Activated Protein Kinases