title: The tetrapeptide Arg-Leu-Tyr-Glu inhibits VEGF-induced angiogenesis.
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.
authors.affiliation: Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea.
authors.forename: Yi-Yong
authors.initials: YY
authors.lastname: Baek
authors.affiliation: Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea.
authors.forename: Dong-Keon
authors.initials: DK
authors.lastname: Lee
authors.affiliation: Department of Biology, Chungnam National University, Daejeon, 305-764, South Korea.
authors.forename: Ju-Hoon
authors.initials: JH
authors.lastname: So
authors.affiliation: Department of Biology, Chungnam National University, Daejeon, 305-764, South Korea.
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea.
authors.forename: Dooil
authors.initials: D
authors.lastname: Jeoung
authors.affiliation: Department of Life Sciences, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea.
authors.forename: Hansoo
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Immunology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea.
authors.forename: Jongseon
authors.initials: J
authors.lastname: Choe
authors.affiliation: Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea.
authors.forename: Moo-Ho
authors.initials: MH
authors.lastname: Won
authors.affiliation: Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea.
authors.forename: Kwon-Soo
authors.initials: KS
authors.lastname: Ha
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-752, South Korea.
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
authors.affiliation: Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea. Electronic address: ymkim@kangwon.ac.kr.
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D015027:Zebrafish
chemical_list: D009842:Oligopeptides; D042461:Vascular Endothelial Growth Factor A; C000602392:arginyl-leucyl-tyrosyl-glutamic acid
keywords: Angiogenesis; ERK; Endothelial cells; Tetrapeptide; eNOS