JTT-705 blocks cell proliferation and angiogenesis through p38 kinase/p27(kip1) and Ras/p21(waf1) pathways

Atherosclerosis. 2005 Oct;182(2):267-75. doi: 10.1016/j.atherosclerosis.2005.02.017. Epub 2005 Apr 7.


The excessive proliferation and migration of vascular smooth muscle cells (SMCs) participate in the growth and instability of atherosclerotic plaque. We examined the direct role of a newly developed chemical inhibitor of cholesteryl ester transfer protein, JTT-705, on SMC proliferation and angiogenesis in endothelial cells (ECs). JTT-705 inhibited human coronary artery SMC proliferation. JTT-705 induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular-signal-regulated kinases (ERK) in SMCs. In addition, the anti-proliferative effects of JTT-705 in SMCs were blocked by p38 MAPK inhibitor. JTT-705 induced the upregulation of p-p21(waf1), and this effect was blocked by dominant-negative Ras (N17), but not by inhibitors of p38 MAPK or ERK. In addition, JTT-705 also induced the upregulation of p27(kip1), and this effect was blocked by p38 MAPK inhibitor. Interestingly, culture medium from JTT-705-treated SMCs blocked human coronary artery EC tube formation in an in vitro model of angiogenesis indirectly via a decrease in vascular endothelial growth factor (VEGF) from SMCs and directly via an anti-proliferative effect in ECs. JTT-705 blocked the proliferation of SMCs through the activation of p38 kinase/p27(kip1) and Ras/p21(waf1) pathways, and simultaneously blocked EC tube formation associated with a decrease in VEGF production from SMCs and an anti-proliferative effect in ECs. Our results indicate that JTT-705 may induce a direct anti-atherogenic effect in addition to its inhibitory effect of CETP activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atherosclerosis / drug therapy
  • Atherosclerosis / pathology
  • Cell Division / drug effects
  • Cells, Cultured
  • Coronary Vessels / cytology
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Endothelium, Vascular / cytology
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Flavonoids / pharmacology
  • Humans
  • Imidazoles / pharmacology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Signaling System / drug effects*
  • Muscle, Smooth, Vascular / cytology
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / pathology*
  • Pyridines / pharmacology
  • Sulfhydryl Compounds / pharmacology*
  • Up-Regulation / drug effects
  • Vascular Endothelial Growth Factor A / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism
  • ras Proteins / metabolism


  • CDKN1A protein, human
  • CDKN1B protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Intracellular Signaling Peptides and Proteins
  • Pyridines
  • Sulfhydryl Compounds
  • Vascular Endothelial Growth Factor A
  • Cyclin-Dependent Kinase Inhibitor p27
  • dalcetrapib
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • ras Proteins
  • SB 203580
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one