Simvastatin suppresses coronary artery endothelial tube formation by disrupting Ras/Raf/ERK signaling.
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.
Miura
Shin-Ichiro
S
Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Matsuo
Yoshino
Y
Saku
Keijiro
K
D018929:Cell Culture Techniques; D003094:Collagen; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007797:Laminin; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D017368:Protein Prenylation / Q000187:drug effects; D011509:Proteoglycans; D019821:Simvastatin / Q000494:pharmacology*
D004338:Drug Combinations; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D019821:Simvastatin; D020928:Mitogen-Activated Protein Kinases