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.

Abstract

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

Substances

  • 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