The tetrapeptide Arg-Leu-Tyr-Glu inhibits VEGF-induced angiogenesis

Biochem Biophys Res Commun. 2015 Aug 7;463(4):532-7. doi: 10.1016/j.bbrc.2015.05.073. Epub 2015 Jun 4.

Abstract

Kringle 5, derived from plasminogen, is highly capable of inhibiting angiogenesis. Here, we have designed and synthesized 10 tetrapeptides, based on the amino acid properties of the core tetrapeptide Lys-Leu-Tyr-Asp (KLYD) originating from anti-angiogenic kringle 5 of human plasminogen. Of these, Arg-Leu-Tyr-Glu (RLYE) effectively inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation, migration and tube formation, with an IC50 of 0.06-0.08 nM, which was about ten-fold lower than that of the control peptide KLYD (0.79 nM), as well as suppressed developmental angiogenesis in a zebrafish model. Furthermore, this peptide effectively inhibited the cellular events that precede angiogenesis, such as ERK and eNOS phosphorylation and nitric oxide production, in endothelial cells stimulated with VEGF. Collectively, these data demonstrate that RLYE is a potent anti-angiogenic peptide that targets the VEGF signaling pathway.

Keywords: Angiogenesis; ERK; Endothelial cells; Tetrapeptide; eNOS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Neovascularization, Physiologic / drug effects*
  • Oligopeptides / pharmacology*
  • Sequence Homology, Amino Acid
  • Signal Transduction / drug effects
  • Vascular Endothelial Growth Factor A / pharmacology*
  • Zebrafish

Substances

  • Oligopeptides
  • Vascular Endothelial Growth Factor A
  • arginyl-leucyl-tyrosyl-glutamic acid